Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:30].[Ca+2].[OH-:32]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:32])(=[O:30])[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Reaction time: 24 h

Procedure:
400 Mg. 8-chloro-3-cyanodibenzo[b,f]-thiepin is dissolved in 30 cc. chloroform and 2 g. m-chloroperbenzoic acid added, and the solution stirred for 24 hours. 5 G. calcium hydroxide is added, the mixture stirred for five minutes and filtered through celite. The organic filtrate is evaporated to dryness and the residue chromatographed on silica gel and eluted with 5% ethyl acetate/benzene mixture to yield 339 mg. (76%) pure sulfone, m.p. 228°-230° C.
Reaction SMILES: CN(C)[C:3](=O)[CH3:4].Br[C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1.C([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=C.CCCCCCCCCCCCCCCC>C(OCC)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH2:9][C:8]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH:13]=[CH:12][CH:11]=1)[CH:3]=[CH2:4]
Reactant: C=COCCCC
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CC(=O)N(C)C
Solvent: CCOCC
Solvent: CCCCCCCCCCCCCCCC
Product: C=CC1(OCCCC)C=CC=C(C(F)(F)F)C1
Temperature: 120 °C

Procedure:
26 mg (0.025 mmol) bis-(dibenzalacetone)-chloroform-palladium and 0.1 mmol of a ligand are placed in a Schlenk-tube under argon. 4 ml N,N-dimethyl-acetamide, 1.12 g (5 mmol) 3-bromo-benzotrifluoride 0.76 g (7.5 mmol) triethyl amine and 0.75 g (7.5 mmol) butyl vinyl ether are added. The reaction mixture is heated to 120° C. for 20 hours. It is cooled to room temperature and 200 mg hexadecane (internal standard) and 15 ml diethylether are added. The mixture is analysed by GC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>CCO.CO.CCOC(C)=O>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(OC)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 7.4 %

Procedure:
To a mixture of 1-(4-methoxyphenyl)-2-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (187 mg, 0.89 mmol), and urea (159 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL). The reaction mixture was refluxed for two days. When TLC (EtOAc:MeOH=10:1) showed that about 30% of the starting materials were consumed, the reaction mixture was concentrated. The residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 20 as a yellow solid (30 mg, yield: 7.5%). 1H NMR (DMSO-d6 300 MHz): δ 10.30 (s, 1H), 8.65 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.20 (s, 1H), 7.09-7.15 (m, 2H), 6.96-7.08 (m, 3H), 6.75-6.82 (m, 4H), 5.12 (s, 1H), 4.00-4.10 (m, 2H), 3.70 (s, 3H), 1.34 (t, J=6.9 Hz, 3H); MS (ESI): m/z 462.0 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].P(Br)(Br)[Br:12]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10]
Reactant: Cc1cccc(CO)c1C
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cc1cccc(CBr)c1C

Procedure:
A mixture of 1-hydroxymethyl-2,3-dimethylbenzene (ref) (5 g) and phosphorous tribromide (1.16 ml) in benzene (50 ml) was heated at reflux for 3 hours. The mixture was diluted with toluene, washed with water, dried (MgSO4) and evaporated. Yield 7 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:12]([CH:11]=[C:7]([C:8]([Cl:20])=[O:9])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)Cl)cc(C(C)(C)C)c1

Procedure:
A mixture of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (9.18 g, 38.9 mmol, prepared by the method of Carter et. al., WO2005021500A1), thionyl chloride (75 mL) and 1 drop of DMF in toluene (200 mL) was heated at reflux for 2 h, cooled and concentrated. The residue was azeotroped with toluene (3×50 mL) and dried under high vacuum to give the title compound as an off-white waxy solid (9.9 g, quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:35]=3[Cl:43])[C:26]2=[O:44])=[C:20]([F:45])[CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt]=O.C(O)C>[NH2:40][C:38]1[CH:37]=[CH:36][C:35]([Cl:43])=[C:34]([N:27]2[C:26](=[O:44])[N:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:10])(=[O:11])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][C:20]=3[F:45])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)[CH:39]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 57 %

Procedure:
A mixture of 313 mg (0.475 mmol) of 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B), 10 mg of platinum oxide, and 4 mL of ethanol was shaken with hydrogen at approximately 3 atm for 2.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated to dryness. The residue was flash chromatographed on about 60 cc of silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) to give a 57% yield of the title compound as a cream-colored solid, mp 208°-210° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[C:43]1([CH2:49][CH2:50][CH2:51][NH2:52])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:43]1([CH2:49][CH2:50][CH2:51][NH:52][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCc1ccccc1)c1ccc(O)cn1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
To a solution of 5-hydroxypyridine-2-carboxylic acid (0.103 g, 0.74 mmol) in dichloromethane was added diisopropylethylamine (0.279 mL, 1.6 mmol), followed by 1-hydroxybenzotriazole monohydrate (0.012 g, 0.8 mmol) and EDCl (0.153 g, 0.8 mmol). The resulting mixture was stirred for 15 minutes and 3-phenyl-1-propylamine (0.108 g, 0.8 mmol) was added. After stirring for 22 h, the reaction mixture was diluted with dichloromethane (80 mL), washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by column chromatography afforded 5-hydroxypyridine-2-carboxylic acid (3-phenylpropyl)amide as white crystals (0.116 g, 61% yield). MS (ES+) m/z 257.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH:26]([NH2:30])([CH2:28][CH3:29])[CH3:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:30][CH:26]([CH2:28][CH3:29])[CH3:27])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CCC(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 12 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (720 mg, 2 mmol) and sec-butylamine (0.7 mL, 7 mmol) in 20 mL of DMF was added PyBOP (1550 mg, 3 mmol) and TEA (3 mL, 15 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was first purified by preparative HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) followed by ISCO CombiFlash Rf silica chromatography eluted with 88:10:2 chloroform:MeOH:H2O to give the desired product as a yellow solid (100 mg, yield 13%). MS calcd for (C19H24BN3O5S): 417.2. MS found (ESI negative): (M−H)−=416.4. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 9.17 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.10 (dd, J=8.4, 2 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.34 (dd, J=8.8, 2.4 Hz, 1H), 5.93 (bs, 2H), 4.87 (s, 2H), 3.78 (s, 2H), 3.71 (m, 1H), 1.40 (m, 2H), 1.05 (d, J=6.4 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[F:17][C:18]([F:52])([F:51])[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:22]=[C:21]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=3)[CH:36]=2)[N:20]=1>C1COCC1>[CH2:1]([NH:8][S:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:37]2[CH:36]=[C:35]([C:21]3[N:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:22]=3)[CH:40]=[CH:39][N:38]=2)[CH:42]=1)(=[O:48])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of benzylamine (0.32 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 85%). MS (ISP) 614.8 [(M+H)+]; mp 202.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN(CCCc2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Yield: 306.3 %

Procedure:
The mixture of 0.08 g (0.22 mmole) of 2-chloro-7,7-difluoro-5-methyl-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-281), 0.069 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.40 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-282) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([CH2:19][OH:20])=[C:11]2[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([CH:19]=[O:20])=[C:11]2[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1
Reactant: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (8.85 mL, 1.1 equivalents) in 150 mL of dry dichloromethane at -78° C. under nitrogen, was added dropwise a solution of dimethylsulfoxide (14.2 mL, 2.2 equivalents) in 125 mL of dichloromethane. After complete addition, the mixture was stirred for five minutes at -78° C. and then a solution of 6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolinemethanol (27.8 ) in 100 mL of dichloromethane and 50 mL of dimethylsulfoxide was added dropwise. This solution was stirred at -78° C. for one hour, after which triethylamine (64.1 mL, 5.0 equivalents) was added. The cooling bath was removed and 400 mL of saturated ammonium chloride solution was added to the reaction mixture.
Reaction SMILES: [Na].[C:2]([NH:5][C:6]#[N:7])(=O)[CH3:3].[CH:8]([CH:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:9].CN(C)C=[O:21]>>[C:6]([N:5]([CH:2]=[CH2:3])[C:9](=[O:21])[CH2:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:7]
Reactant: CC(=O)NC#N
Reactant: CN(C)C=O
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na]
Product: C=CN(C#N)C(=O)CCc1ccccc1

Procedure:
23.3 g (0.2 mol +10% excess) of the sodium salt of acetylcyanamide and 30.5 g (0.2 mol) of vinylbenzyl chloride (technical mixture of isomers containing approx. 40% of the para-component and 60% of the meta-component) are reacted in 100 ml of dimethylformamide for 8 hours at 48°-50° C., when the reaction is complete the mixture is filtered with suction, the filtrate is introduced into 300 g of ice and 500 ml of water while stirring vigorously and the mixture is then extracted with ethyl acetate. The ethyl acetate solution is dried with anhydrous sodium sulfate and filtered with suction, the filtrate is decolourised with active charcoal, the solution is filtered and the filtrate is concentrated in vacuo at 40° C. on a rotary evaporator. The residue is dried to constant weight at 40° C./0.13 mbar. This gives 34.9 g (87.1% of theory) of a brownish, viscous liquid, which is purified by bulb tube distillation at 130°-145° C./0.7 mbar.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[C:7][CH2:8][OH:9])=[CH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([O:9][CH2:8][C:7]#[C:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)(=[O:12])[CH3:11]
Reactant: OCC#Cc1ccoc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCC#Cc1ccoc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 3-(3-furyl)-2-propynyl alcohol (1.45 g, 0.0118 mol), DMAP (1 mg), TEA (2.46 ml, 0.017 mol), and acetic anhydride (1.6 ml, 0.017 mol) in 25 ml of methylene chloride was stirred for 1 hour and the mixture was poured into cold 1 N HCl solution. The mixture was extracted with ether (3×50 ml), the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (hexane/ether, 2:1) to afford 1.44 g (57.5%) of 3-(3-acetyloxy-1-propynyl)furan as a clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1)#[CH:2].CO[C:12](=[O:30])[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16](Cl)=[N:15][CH:14]=1.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38]>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][C:16]2[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=3)=[CH:18][C:13]([C:12]([NH:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]3[OH:38])=[O:30])=[CH:14][N:15]=2)=[N:4][CH:5]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C#Cc1ccc(F)cn1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2ccc(F)cn2)c(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 140, using 2-ethynyl-5-fluoro-pyridine (CAN 884494-34-2), 6-chloro-5-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester, and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials, LC at 215 nm; Rt 4.26: 95%, m/z (ES+): 488.5 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:30](=[O:34])[CH:31]([CH3:33])[CH3:32]>>[CH:27]([OH:26])=[O:34].[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC(C)C)C3)cc1
Product: O=CO

Procedure:
Method as example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2 yl)phenyl)urea (example 13) and isobutyraldehyde as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2Cl)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.ClCCl>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
Combine 1-(4-fluorobenzyl)-2-chloro-1H-benzimidazole (22.1 g, 84 mmol) and ethyl 4-aminopiperidine-1-carboxylate (27.7 g, 161 mmol) and heat to 170° C. After 4 hours, partition the reaction mixture between aqueous 2.5M sodium hydroxide solution and chloroform. Separate the layers and extract the aqueous layer twice with chloroform. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on a short column of silica gel eluting sequentially with dichloromethane and then 15% ethyl acetate/dichloromethane. Evaporate the product containing fractions, triturate with hexane, filter, and dry to give (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49](O)#[C:50][CH2:51][CH2:52][OH:53].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:49][C:50]#[C:51][CH2:52][OH:53])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OC#CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CC#CCO)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (393 mg), 1,4-butyne diol (0.45 gm) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room temperature overnight, concentrated under reduced pressure and adsorbed onto silica gel. The crude product is purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from methanol-acetonitrile to afford 0.16 gm of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[OH2:16].[C:17]1(C)C=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH:21]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: OCCOc1ccc(Br)cc1C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Br)ccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2164 %

Procedure:
A mixture of 2-(4-bromo-2-(trifluoromethyl)phenoxy)ethanol (16 g), 3,4-dihydro-2H-puran (9.5 g) and p-toluenesulfonic acid hydrate (0.5 g) in THF (100 ml) was stirred at room temperature for 1 hour then diluted with 5% sodium bicarbonate (300 ml) and extracted with ethyl acetate (500 ml). Organic layer was then dried over sodium sulphate, solvent removed under vacuum to give expected product (21 g).
Reaction SMILES: [BrH:1].N[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOCC>[Br:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Br
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 48% aqueous HBr (2.31 ml, 20 mmol) dissolved in DMSO (25 ml) was added dropwise to a solution of 4-aminobenzophenone (0.986 g, 5 mmol) in a mixture of 25 ml of DMSO and KNO2 (0.851 g, 10 mmol) at 35° C. with agitation. The added mixture was stirred at 35° C. for 10 minutes, and then transferred to a solution containing K2CO3 (5 g) in 100 ml ice-water. The reaction mixture was then taken up in ether, and then the ethereal extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude 4-bromobenzophenone. The crude product was further purified by column chromatography to obtain 4-bromobenzophenone. The yield determined by gas chromatography was 72% (based on decane as an internal standard).