Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (318 mg) in CH2Cl2 (10 mL) containing Et3N (91 mg) was added methanesulfonyl chloride (70 μL) and the mixture was stirred at room temperature for 1 hour. The solution was washed with water, with brine and dried over Na2SO4, filtered and evaporated. The solid obtained was recrystallized from CH3CN to give the title compound (170 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[C:33]([CH2:32][C:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:34]
Reactant: N#CCBr
Reactant: CCOC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (0.28 g, 1.00 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (1.00 mL, 1.00 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (0.69 mL, 1.00 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes), to obtain the title compound. MS (DCI+) m/z 333 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([F:15])[CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].CO>[F:15][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:13]([OH:14])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: C=CCc1cc(F)c2cccnc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(F)c2cccnc2c1O
Yield: 96.4 %

Procedure:
After a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser and a thermometer was replaced with Ar, 40.0 mL of methanol, 5 wt % Pd/C (0.40 g) and 7-allyl-5-fluoro-8-quinolinol (4.09 g) were thrown thereto and the mixture was stirred under slight pressurization of hydrogen. After replaced with Ar, the mixture was filtered to remove Pd/C and the filtrate was concentrated to give 3.98 g of 5-fluoro-7-propyl-8-quinolinol as a pale purple solid (yield: 96.0%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Br)n1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 6-bromopyridine-2-carbaldehyde (10.40 g, 53.76 mmol) in MeOH (120 mL) was treated with sodium borohydride (2.04 g, 53.76 mmol), stirred for 1 h and partitioned between EtOAc and water. The organic phase was separated and the aqueous re-extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (9.76 g, 97%) as a pale-yellow liquid; LC-MS retention time 1.52 min, (M+H)+ 188 and 190.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=O)[C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:48]2)=CC=1>CCOC(C)=O>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)=[S:48])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)cnc1C(=S)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 120 °C
Yield: 12.2 %

Procedure:
A sealable vial was charged with N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide (Example 4, 0.068 g, 0.147 mmol) and toluene (1 mL). 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (0.059 g, 0.147 mmol) was added and the reaction mixture was heated to 120° C. overnight. Upon cooling to room temperature, the reaction mixture was taken up in EtOAc (75 mL). The organic layer was washed with aqueous saturated NaHCO3 and with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified through silica gel (gradient 30%-50% EtOAc-hexane) affording the title compound as a yellow solid (8.4 mg, 0.018 mmol, 12%). MS m/z=479 [M+H]+. Calculated for C19H16ClF5N4OS: 478.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O)[OH:8])[OH:6])=[O:3].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9][N:21]=[N+:22]=[N-:23])[OH:8])[OH:6])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-]
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of methyl-2-deoxy-5-O-tosyl-D-ribose (13.6 g, 45 mmol) in DMF (250 mL) was added sodium azide (4.4 g, 67 mmol). The mixture was refluxed for 4 hours, cooled to room temperature, quenched with ice water (1.5 mL), and extracted with ethyl-acetate. The extract was washed with water, dried, and concentrated to give an oil (6.2 g, 86% yield). NMR
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[OH:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(F)c3)nc3ccccc23)n[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)c(F)c3)nc3ccccc23)n[nH]1
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To crude (3,4-difluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (553 mg, 1.5 mmol) in 1:1 MeOH/THF (40 mL) at 0° C. was added sodium borohydride (0.09 g, 2.4 mmol), and the solution was stirred for 30 min, after which 6N HCl was added. The mixture was concentrated to dryness, and ca. 2/3 of the residue was purified by silica gel chromatography eluting with 0-15% MeOH/DCM to afford (3,4-difluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol (34 mg). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H) 6.03 (s, 1H) 6.22 (s, 1H) 7.45-7.55 (m, 2H) 7.66 (t, 1H) 7.78 (t, 1H) 8.07 (t, 1H) 8.19 (t, 1H) 8.82 (d, 1H) 12.09 (bs, 1H) 12.67 (bs, 1H); LC-MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:22][CH:21]=1.[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>ClCCl>[CH3:39][CH:38]([S:41]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:22][CH:21]=1)(=[O:43])=[O:42])[CH3:40]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccccc2CN)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)NCc1ccccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1

Procedure:
Add 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) drop wise (85 mg, 0.6 mmol) to a suspension of propane-2-sulfonic acid [2-(2′-aminomethyl-biphenyl-4-yl)-thiophen-3-yl]-amide (57 mg, 0.15 mmol) in dichloromethane (2 ml) at 0° C., followed by drop wise addition of isopropylsulfonyl chloride (42 mg, 0.3 mmol) and stir the reaction at room temperature overnight. Remove solvent under reduce pressure. Purify with flash chromatography (Silica gel-hexane/EtOAc). Concentrate the desired fractions to provide propane-2-sulfonic acid (2-{2′-[(propane-2-sulfonylamino)-methyl]-biphenyl-4-yl}-thiophen-3-yl)-amide. MS (m/e): 491.1(M−1), propane-2-sulfonic acid (2-{2′,2′-bis-[(propane-2-sulfonylamino)-methyl]-biphenyl-4-yl}-thiophen-3-yl)-amide. MS (m/e): 510.2(M−1).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][CH2:18][C:17](=O)[C:16]=2[CH:23]=1>O.C(O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][CH2:18][C:17](=[N:2][OH:3])[C:16]=2[CH:23]=1
Reactant: COc1ccc2c(c1)C(=O)CCCO2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=NO)CCCO2
Reaction time: 24 h

Procedure:
6.95 g of hydroxylamine hydrochloride dissolved in 15 ml of water and 5.3 g of sodium carbonate are added to a solution of 19.2 g of 7-methoxy-3,4-dihydro-1-benzoxepin-5-one in 45 ml of ethanol. The mixture is left at room temperature for 24 hours with stirring. 100 ml of water are then added and the alcohol is evaporated. The aqueous solution is make alkaline by the addition of soda and unreacted benzoxepin is extracted with ether. The aqueous phase is neutralised and the desired oxime is extracted with ether. After drying of the organic solution and evaporation of the solvent under reduced pressure, a white solid is obtained which, when recrystallised from cyclohexane yields 17 g of the desired pure product which has a melting point of 103° to 104° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][C:10]=2[CH2:21][NH:22][CH3:23])[CH2:15][CH2:16]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Reactant: NCc1ccccc1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and benzylamine. Colourless oil. Rf value: 0.45 (alumina, petroleum ether/ethyl acetate=2:1, v:v).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][O:17][CH3:18]>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 908.6 %

Procedure:
Prepared from tert-butyl piperazine-1-carboxylate (1.02 g, 5.50 mmol) and 1-bromo-2-methoxyethane (0.695 g, 5.0 mmol) according to the procedure described for Example 138, Step A. The product was obtained as a waxy solid (11.10 g, 89%).
Reaction SMILES: CO[C:3](OC)([N:5]([CH3:7])[CH3:6])C.[C:10]([O:13][C@@H:14]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:25][S:24][C@H:15]1[O:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:12])[CH3:11]>C(O)C>[CH3:3][N:5]([CH3:7])[CH:6]=[N:23][C:18]1[C:17]([O:16][C@@H:15]2[S:24][CH2:25][C@@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:14]2[O:13][C:10](=[O:12])[CH3:11])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1N
Solvent: CCO
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1N=CN(C)C
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
0.31 g (2.6 mM) of 1,1-dimethoxy-N,N-dimethylethanamine (N,N-dimethylformamide dimethylacetal) is added to a solution of 1 g (2.6 mM) of 2-amino-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Preparation 1) in 10 ml of ethanol. The mixture is heated, in a microwave-compatible container, with stirring at 120° C. for 20 minutes in a microwave oven. The reaction mixture is subsequently concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with ethyl acetate. The desired product is obtained in the form of a white solid with a yield of 46%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:13]([F:16])([F:15])[F:14])[N:4]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]([F:15])([F:14])[F:16])[N:4]=1
Reactant: FC(F)(F)C1Cc2ccccc2C(CCl)=N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)cc2ccccc12

Procedure:
Prepared by treating 905 mg of 1-chloromethyl-3-trifluoromethyl-3,4-dihydro-isoquinoline with 420 mg of potassium-tert. butoxide in 10 ml of tetrahydrofuran at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH2:4][C:3]3[C:2](=[C:22]([F:23])[CH:21]=[CH:20][CH:19]=3)[NH:1][C:24]2=[O:25])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-amino-3-fluorobenzyl)-1-benzylpiperidin-4-amine (36.3 g, 116 mmol) in tetrahydrofuran (600 mL) at room temperature was added carbonyl diimidazole (20.7 g, 1.10 equiv) in one portion. The reaction was stirred at room temperature for 3 h, heated at reflux for 30 min, and concentrated. The resulting solid was dissolved in 1:1 diethyl ether/ethyl acetate, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give the crude product as a wet, yellow solid. The solid was triturated with diethyl ether and filtered to give 30.0 g (76%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 1.68 (m, 2H), 1.86 (dddd, J=11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, J=11.6, 10.1, 2H), 2.98 (d, J=11.6, 2H), 3.51 (s, 2H), 4.34-4.44 (m, 3H), 6.71 (bs, 1H), 6.79-6.89 (m, 2H), 6.94 (dd, J=9.2, 9.2, 1H), 7.21-7.34 (m, 5H). Mass spec.: 340.30 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)(Cl)Cl)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: Clc1cc(Cl)cc(C(Cl)(Cl)c2cc(Cl)cc(Cl)c2)c1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Product: CCOC(=O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2

Procedure:
This compound was prepared from bis-(3,5-dichlorophenyl)dichloromethane and ethyl 3,4-dihydroxybenzoate according to Example 269d; light red solid, m.p.: 89° C.;
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6].[CH2:24](I)[CH3:25]>C(O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:24][CH3:25])[S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6]
Reactant: CCI
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1C(C(=O)OC)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
33 ml of 1 N sodium hydroxide were added dropwise over a period of 25 minutes to a suspension of 10.1 gm (0.033 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 20 gm (0.12 mol) of ethyl iodide in 400 ml of aqueous 75% ethanol, whereby the starting material went completely into solution. The reaction mixture was then stirred at room temperature for 30hours. Thereafter, the crystals which had formed were collected by filtration and washed with a small quantity of ethanol, yielding 8.7 gm (79% of theory) of the desired compound, m.p. 179° C (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:32]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:10]=[O:32])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2-(3,4-Dichlorophenyl)-3-(1,3-dioxolan-2-yl)propanenitrile (64 g) (see Preparation 13) was suspended in anhydrous toluene (500 ml) and cooled to −70° C. under a nitrogen atmosphere. Diisobutylaluminium hydride (200 ml of a 1.5M solution in toluene) was then added over 50 minutes, by which time a clear solution was achieved. The mixture was stirred at −70° C. for a further 30 minutes and then allowed to warm slowly to −20° C. Water (24 ml) was carefully added (exothermic reaction) before pouring the mixture into a 15% (by weight) aqueous solution of citric acid (1800 ml). Toluene (100 ml) was added and the mixture was vigorously stirred for 1 hour. The resulting emulsion was filtered through a short column of Arbacel (trade mark) filter aid to give two clear phases which were separated. The organic phase was washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-al as a yellow oil (53.5 g)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17](O)=[O:18])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:31]=[C:32]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[NH2:33])[CH:29]=1>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:33][C:32]4[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:30]([N:28]5[CH:29]=[C:25]([CH3:24])[N:26]=[CH:27]5)[CH:31]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH:25]1([C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][CH:33]=2)[CH2:27][CH2:26]1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([CH:25]5[CH2:27][CH2:26]5)[CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CC1(C)OB(c2cccc(C3CC3)c2)OC1(C)C
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C5CC5)c4)cc32)N=C1N
Yield: 2.9 %

Procedure:
Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (110 mg, 0.29 mmol) in 1,4-dioxane (5.0 mL), Cs2CO3 (2 N, 1 mL) and 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.29 mmol) The mixture was refluxed for 2 hour. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 2′-amino-6-(3-cyclopropylphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (3.6 mg, 3%). 1H-NMR (MeOD): 0.71 (m, 1H), 0.98 (m, 1H), 1.97 (m, 1H), 2.31 (m, 1H), 2.65 (m, 0.8H), 2.75 (m, 0.2H), 3.32 (m, 3H), 5.24 (m, 0.2H), 5.86 (m, 0.8H), 6.99 (m, 1H), 7.12 (m, 2H), 7.23 (m, 2H), 7.28 (m, 2H), 7.46 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: OCc1nc2cc(Cl)cnc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Preparation 59 was repeated, except that 3.00 g of 6-chloro-2-hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 63), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.03 ml of methyl iodide and 50 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.87 g of the title compound, melting at 141°-142° C.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1Cl
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)cc1Cl
Temperature: 130 °C
Yield: 14.8 %

Procedure:
To the solution of 2-{4-[(3-chloro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (150 mg, 0.359 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (85 mg, 0.431 mmol) in NMP (2 mL), was added K2CO3 (198 mg, 1.436 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (24 mg, 14.82% yield). LCMS: rt=3.35 min, [M+H+]=451