Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15]>>[OH:15][CH2:14][C@@H:13]1[CH2:16][CH2:17][CH2:18][N:12]1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OC[C@@H]1CCCN1
Product: OC[C@@H]1CCCN1c1ccc2ccccc2n1
Yield: 107.5 %

Procedure:
The title compound (6 g, 100%) was prepared as a syrupy liquid from 2-chloroquinoline (4 g) and L-prolinol (14.8 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]#[N:12])=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]#[N:12])=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: N#Cc1c[nH]c2cccc(Br)c12
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 4-bromo-1H-indole-3-carbonitrile LVII (2 g, 9.05 mmol), ethyl cinnamate (3.19 g, 18.1 mmol), tetrabutylammonium bromide (582 mg, 1.81 mmol), TEA (2.52 ml, 18.1 mmol) and palladium-dichloro-[bis-(tri-ortho-tolyl)phosphine] (357 mg, 0.453 mmol) in a sealed vial was stirred at 110° C. for 20 hours. The reaction mixture was cooled to room temperature, partitioned between H2O and DCM, and the aqueous layer was extracted with DCM. The organic extracts were combined, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII as a yellow solid (1.57 g, 55% yield).
Reaction SMILES: C(Cl)(Cl)=O.NC1C=CC2N(C)[C:14](=[O:17])[C@H:13](C)[N:12]=C(C3C=CC=CC=3F)C=2C=1Cl.[Cl:28][C:29]1[C:34]2[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[N:36][C@@H:37]([CH3:42])[C:38](=[O:41])[N:39]([CH3:40])[C:33]=2[CH:32]=[CH:31][C:30]=1[N:50]=[C:51]=[O:52].NCCO>ClCCCl.C(N(CC)CC)C>[Cl:28][C:29]1[C:34]2[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[N:36][C@@H:37]([CH3:42])[C:38](=[O:41])[N:39]([CH3:40])[C:33]=2[CH:32]=[CH:31][C:30]=1[NH:50][C:51]([NH:12][CH2:13][CH2:14][OH:17])=[O:52]
Reactant: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O
Reactant: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N=C=O)c2Cl)N(C)C1=O
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: NCCO
Product: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(NC(=O)NCCO)c2Cl)N(C)C1=O
Temperature: 0 °C

Procedure:
A solution of 2 g of phosgene in 20 ml of ice-cold 1,2-dichloroethane is placed in a sulphonation flask. There is added dropwise thereto a solution of 4 g (0.012 M) of (S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 40 ml of 1,2-dichloroethane while cooling with ice and stirring in such a manner that the temperature does not exceed 10° C. The mixture is then stirred at room temperature for 45 minutes. The resulting solution of (S)-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate is cooled with ice and slowly made alkaline with 6 ml of triethylamine. A solution of 2 ml of 2-aminoethanol in 20 ml of 1,2-dichloroethane is treated with the foregoing pre-prepared solution, the mixture is stirred at room temperature for 30 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then methylene chloride/ethanol (20:1) as the eluting agent and crystallised from a small amount of ethyl acetate/n-hexane. There is obtained (S)-1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which melts above 147° C. with decomposition; [α]25D =+192.2° (in dioxan; 1%).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.Cl[C:46]([O:48][CH2:49][CH3:50])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:46](=[O:47])[O:48][CH2:49][CH3:50])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added ethyl chloroformate (3.7 μL, 0.039 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C20H27N4O3S (M+H)+: m/z=403.2. Found: 402.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:20]([Cl:19])[CH:21]=2)=[CH:27][CH:28]=1)#[N:2]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (360 mg, 1.44 mmol) from Step A and 3,4-dichloro-N-(4-hydroxyphenyl)benzamide (488 mg, 1.73 mmol) from Step B in DMSO (4 ml) was added K2CO3 (240 mg, 1.73 mmol). The reaction was stirred at 125° C. overnight, then cooled to ambient temperature and diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organics washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified on a Biotage Horizon (40+M 5% to 50% B:EtOAc, 21 ml-1008 ml). The appropriate fractions were then combined and concentrated to give tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoate (0.476 g, 0.797 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.84 (bs, N—H), 7.72 (d, J=9.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.60 (m, 2H), 7.42 (d, J=8.6 Hz, 1H), 7.11 (d, J=7.7, 2H), 6.83 (d, J=8.7 Hz, 1H), 3.61 (q, J=7.1 Hz, 1H), 1.45 (d, J=7.5 Hz, 3H), 1.42 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1>>[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=3)=[N:3][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: Cc1nccc(N)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1nccc(Nc2ncc(-c3cccc(S(C)(=O)=O)c3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=412.3 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), (3-methylsulfonylphenyl)boronic acid and 4-amino-2-methylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:24][CH:25]=[CH2:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:26][CH:25]=[CH2:24])[C:10]([OH:12])=[O:11]
Reactant: C=CCBr
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: C=CCC(C(=O)O)c1ccc(Cl)cc1Cl

Procedure:
Step AB (1): 2-(2,4-Dichlorophenyl)acetic acid was deprotonated with NaHMDS and reacted with 3-bromoprop-1-ene using a procedure analogous to Step AA (1) to afford 2-(2,4-dichlorophenyl)pent-4-enoic acid as a clear viscous oil. LC-MS (M−H)− 243.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.42 (d, J=2.14 Hz, 1 H) 7.31-7.36 (m, 1 H) 7.25 (dd, J=8.24, 2.14 Hz, 1 H) 5.67-5.77 (m, J=17.05, 10.19, 6.83, 6.83 Hz, 1 H) 5.07 (dd, J=17.09, 1.53 Hz, 1 H) 5.04 (d, J=10.38 Hz, 1 H) 4.26 (t, J=7.48 Hz, 1 H) 2.81 (dt, J=14.34, 7.17 Hz, 1 H) 2.55 (dt, J=14.57, 7.21 Hz, 1 H).
Reaction SMILES: C1(CN2C(=O)C3NC(N)=NC=3N(CC3CC3)C2=O)CC1.[CH:21]1([CH2:24][N:25]2[C:34](=[O:35])[C:33]3[NH:32][CH:31]=[N:30][C:29]=3[N:28]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:26]2=[O:27])[CH2:23][CH2:22]1.[N+:40]([O-])([OH:42])=[O:41]>>[CH:21]1([CH2:24][N:25]2[C:34](=[O:35])[C:33]3[NH:32][C:31]([N+:40]([O-:42])=[O:41])=[N:30][C:29]=3[N:28]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:26]2=[O:27])[CH2:23][CH2:22]1
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: O=[N+]([O-])O
Agent: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Product: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
A process for making 1,3-dicyclopropylmethyl-8-amino xanthine which process comprises reacting 1,3-dicyclopropylmethyl xanthine with nitric acid to yield 1,3-dicyclopropylmethyl-8-nitro xanthine and thereafter reducing the nitro group to an amino group to yield 1,3-dicyclopropylmethyl-8-amino xanthine.
Reaction SMILES: C1CCCCC=1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[C:23](Br)=[CH:22][N:21]=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:17])([O-])=O.O.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[NH2:7][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:17]
Reactant: COc1cc(C(=O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1cc(C(=O)c2ccccc2N)ccn1
Yield: 99.2 %

Procedure:
Cyclohexene (21 ml) was added to a stirred mixture of (2-nitrophenyl)-(5-bromo-2-methoxypyridin-4-yl)methanone (2.16 g) in ethanol (210 ml). A water slurry of 10% palladium on carbon (216 mg) was added followed by sodium acetate (524 mg). The suspension was heated to reflux for 4.5 hours then the mixture was cooled, filtered and evaporated to dryness. The residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous re-extracted with dichloromethane (twice). The combined organics were washed with water, brine, dried (sodium sulphate) then evaporated to dryness to give the title compound as a yellow solid (1.45 g). mp 82°-86° C. Rf =0.7 in 5% methanol/dichloromethane on silica plates; 1H NMR (360 MHz, CDCl3) δ 3.99 (3H, s), 6.57 (1H, ddd, J=1 and 7 Hz), 6.72 (1H, d, J=7 Hz), 6.86 (1H, s), 7.00 (1H, dd, J=1 and 5 Hz), 7.31 (1H, ddd, J=1 and 7 Hz), 7.37 (1H, dd, J=1 and 7 Hz), 8.26 (1H, d, J=5 Hz), IR (KBr) 3450, 3350, 1640 and 1620 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:15]2[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].CC1C=CC(S(O[CH2:43][CH:44]2[CH2:47][CH2:46][O:45]2)(=O)=O)=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([N:20]([CH2:43][CH:44]3[CH2:47][CH2:46][O:45]3)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCO3)C(=O)OC(C)(C)C)c(SC)nn12
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (100 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, the mixture was stirred for 30 minutes, 2-oxetanylmethyl 4-methyl-1-benzenesulfonate (70 mg) was added and the mixture was stirred for 1 hour at 40° C. 2-Oxetanylmethyl 4-methyl-1-benzenesulfonate (23 mg) [CAS No. 115845-51-7] and sodium hydride (60%, 5 mg) were again added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure to obtain crude tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)carbamate. This was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (8 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]4)=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:13]2[N:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)[CH2:17]1)(=[O:32])=[O:31]
Reactant: c1cc2nnc(C3CCCNC3)n2nc1N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(c2nnc3ccc(N4CCCCC4)nn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution mixture of 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo[4,3-b]pyridazine (670 mg), triethylamine (360 mg) and methylene chloride (15 ml), methanesulfonyl chloride (320 mg) was added and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant crude crystals were recrystallized from ethanol to obtain 3-(1-methanesulfonylpiperidin-3-yl)-6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazine (230 mg) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:11][C:10]([CH3:13])=[CH:9][C:8](=[O:14])[C:7]=2[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1)=O.[C:17]([O:23][CH:24]([CH3:26])[CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.[NH2:27]/[C:28](/[CH3:32])=[CH:29]\[C:30]#[N:31].C(O)(=O)C>CC(O)C>[C:30]([C:29]1[CH:1]([C:3]2[CH:4]=[CH:5][C:6]([C:15]#[N:16])=[C:7]3[C:12]=2[O:11][C:10]([CH3:13])=[CH:9][C:8]3=[O:14])[C:18]([C:17]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[C:19]([CH3:21])[NH:27][C:28]=1[CH3:32])#[N:31]
Reactant: C/C(N)=C/C#N
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: Cc1cc(=O)c2c(C#N)ccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc(C#N)c3c(=O)cc(C)oc23)C(C(=O)OC(C)C)=C(C)N1

Procedure:
21 mg (0.09 mmol) of 8-formyl-2-methyl-4-oxo-4H-chromene-5-carbonitrile are dissolved with 14 mg (0.09 mmol) of isopropyl acetoacetate, 8 mg (0.09 mmol) of 3-aminocrotononitrile and 6 mg (0.09 mmol) of acetic acid in 2 ml of 2-propanol and heated under reflux under argon for 6 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 8.8 mg (22% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[C:11](F)=[C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[CH:8][C:7]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27]>CN1C(=O)CCC1.CO.C(Cl)Cl>[Cl:5][C:6]1[C:11]([NH:4][CH2:3][CH2:1][OH:2])=[C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH:9]=[CH:8][C:7]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: NCCO
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)c(NCCO)c1Cl)C(F)(F)F
Temperature: 120 °C
Yield: 33.9 %

Procedure:
Ethanolamine (47 mg, 2.5 eq) was added to a solution of (R)-N-(2-chloro-3-fluoro-4-{4-fluorophenylsulphonyl}phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 11) (135 mg) in NMP (1 ml) and the mixture was stirred and heated (oil bath 120° C.) under argon for 24 hours. The reaction mixture was cooled and partitioned between a saturated aqueous solution of ammonium chloride (10 ml) and ether (3×20 ml). The combined ether extracts were washed with water (50 ml), dried and concentrated to give a gum. The residue was dissolved in MeOH/DCM and loaded onto deactivated silica (1 g). It was then concentrated to give a free flowing powder which was poured onto an ISOLUTE column (10 g silica) and chromatographed eluting with EtOAc/isohexane to give the title compound (50 mg) as a gum. NMR: 1.65 (s, 3H), 3.2 (m, 2H), 3.42 (m, 2H), 4.92 (t, 1H), 5.91 (t, 1H), 7.47 (t, 2H), 7.89 (d, 1H), 7.96-8.08 (m, 3H), 9.85 (brs, 1H); m/z: 483.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.[CH:15]1([CH:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH2:17][CH2:16]1.O>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]([CH:15]2[CH2:17][CH2:16]2)[C:19]([N:5]2[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]2=[O:9])=[O:20])=[CH:27][CH:26]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a separate reaction vessel a stirred solution of 2.0 grams (0.016 mole) of (S)-4-(1-methylethyl)-2-oxazolidinone in 50 mL of tetrahydrofuran was cooled to -78° C., and 6.25 mL (0.016 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred for 30 minutes, and then the 2-cyclopropyl-2-(4-chlorophenyl)acetyl chloride, prepared above, was added dropwise during several minutes. Upon completion of addition, the reaction mixture was stirred for an additional 30 minutes and then was poured into water. The organic layer was separated and washed with one portion of aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to chromatography on silica gel using hexane:diethyl ether (3:1) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.85 gram of diastereomer (A) and 0.8 gram of diastereomer (B) of (S)-N-[2-(4-chlorophenyl)-2-cyclopropylacetyl]-4-(1-methylethyl)-2-oxazolidinone. Upon standing, diastereomer (A) crystallized to a solid, m.p. 61°-64° C.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)O1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:31]3[CH:36]=[N:35][C:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:33][CH:32]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2cc(Cl)ccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cc(F)c(-c3ccc(N4CCOCC4)nc3)nc2C=Cc2cc(Cl)ccc21
Yield: 64.5 %

Procedure:
The title compound (21.6 mg, 64.3%) was prepared from 9C (24.4 mg, 0.072 mmol) and 5A (22 mg, 0.072 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.649 min; LCMS Found: (M+H)+=465.
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.CC1CCOC1.C(C1[C:29]([OH:30])=[C:28](C(C)(C)C)C=C(C)C=1)(C)(C)C.[C:36]([O:40]CCO)(=[O:39])[CH:37]=[CH2:38].[N-]=C=O>O1CCCC1>[C:36]([OH:40])(=[O:39])[CH:37]=[CH2:38].[NH2:8][C:9]([O:30][CH2:29][CH3:28])=[O:10]
Reactant: C=CC(=O)OCCO
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CC1CCOC1
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
Into a reaction vessel equipped with a stirrer were charged 5.5 parts of tolylene diisocyanate, 42.0 parts of a ring-opening copolymer from tetrahydrofuran and 3-methyltetrahydrofuran, having a number average molecular weight of 2,000, and 0.01 part of 2,6-di-t-butyl-p-cresol, as a polymerization inhibitor. The mixture was cooled with ice to a temperature of below 10° C., while stirring. When the temperature was lower than 10° C., 0.04 part of dibutyltindilaurate was added and the mixture was stirred for 2 hours while controlling the temperature at 20-30° C. Then, after the addition of 2.2 parts of hydroxyethyl acrylate, the mixture was stirred for 4 hours at 50-60° C., until the amount of remaining isocyanate is 0.1% by weight or less. The Liquid urethane acrylate obtained in this manner is hereinafter referred to as UA-2.
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=3[S:6][C:5]=12.[Br:14]C(C)(C)C.CN(C)[CH:21]=[O:22]>O>[BrH:14].[N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([NH:13][CH:21]=[O:22])=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: CN(C)C=O
Reactant: CC(C)(C)Br
Reactant: Nc1ccc2c(c1)SC1=NCCN12
Solvent: O
Product: Br
Product: O=CNc1ccc2c(c1)SC1=NCCN12
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 3 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-7-amine, 15 parts of 2-bromo-2-methylpropane and 13.5 parts of N,N-dimethylformamide is stirred for 20 hours at 80° C. The reaction mixture is poured onto 50 parts of water. The precipitated product is filtered off, washed successively with water, 2-propanol and 2,2'-oxybispropane, and dried, yielding 3 parts of N-(2,3-dihydroimidazo[2,1-b]benzothiazol-7-yl)formamide monohydrobromide; mp. 287.3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>CCOCC>[N+:8]([C:6]1[CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc([N+](=O)[O-])cc(N)n1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1cc([N+](=O)[O-])cc(NC(=O)CCl)n1
Reaction time: 0.33 h

Procedure:
A solution of 2-amino-4-nitro-6-ethoxypyridine (29.4 grams) in absolute ether (150 ml), and pyridine (25 grams) are charged into a glass reaction vessel equipped with stirrer, thermometer and addition funnel. The mixture is cooled to a temperature of about 0° C and chloroacetyl chloride (11.3 grams) dissolved in ether (50 ml) is then slowly added thereto with stirring over a period of about 20 minutes. Stirring and cooling are continued for an additional period of about 30 minutes. The resulting precipitate is then recovered from the reaction medium by filtration, is washed first with aqueous sodium carbonate and then with water, and is dried to yield the desired product N-(4-nitro-6-ethoxy-2-pyridyl)-α-chloroacetamide.