Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][O:4]/[N:5]=[C:6](/[C:23]1[N:24]=[C:25]([NH:28]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:26][CH:27]=1)\[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])#[N:2].O>C(O)=O>[NH2:28][C:25]1[S:26][CH:27]=[C:23](/[C:6](=[N:5]/[O:4][CH2:3][C:1]#[N:2])/[C:7]([OH:9])=[O:8])[N:24]=1
Reactant: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: N#CCO/N=C(\C(=O)O)c1csc(N)n1

Procedure:
Diphenylmethyl (Z)-2-cyanomethoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (lg) was dissolved in formic acid (98%, 40 ml) and water (10 ml) at room temperature and stirred for 12 h. The solvent was removed in vacuo and the residue triturated with ether to give the title compound as an off-white solid (0.39 g). The product was sufficiently pure for the next step; νmax (nujol) 3700-2500, 1605 (broad), 1465 and 1380 cm-1 ; δH inter alia 5.09 (2H, s), 7.04 (1H, s). [Mass spectrum: EI M+ (226)].
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].C(O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][O:20][C:7]1[C:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)OCC)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)O)oc12
Reaction time: 2 h

Procedure:
A suspension of 12.05 parts of 8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester in 225 parts of ethanol was treated with 0.2 parts of 5% palladium/charcoal catalyst and hydrogenated at a pressure of 4 atmospheres. After 30 minutes the hydrogen uptake ceased and the reaction mixture was filtered. The volume of the filtrate was reduced and then water was added. On standing 10.2 parts of 5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester crystallised as yellow needles, melting point 64.5°-65° C. This material was stirred with a hot aqueous solution of sodium bicarbonate containing some ethanol for two hours. The resulting solution was cooled, washed with diethyl ether and acidified with dilute hydrochloric acid. The yellow precipitate was collected and crystallised from aqueous ethanol to give 7.2 parts of 5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid as yellow needles, melting point 166°-167° C.
Reaction SMILES: [OH:1][CH:2]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.CO.[2H]C([2H])([2H])C#N.[2H]O[2H]>C(#N)C.ClCCl>[CH3:11][N:10]1[C:9](=[O:12])[C:8]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:7]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[N:6]=[C:5]1[NH:4][CH2:3][C:2](=[O:1])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(NCC(O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [2H]C([2H])([2H])C#N
Agent: [2H]O[2H]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: Cn1c(NCC(=O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reaction time: 0.05 h

Procedure:
To a striring suspension of 2-(2-hydroxy-3-phenyl-propylamino)-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (150 mg, 0.32 mmol) in 5 mL dry acetonitrile and 5 mL dichloromethane was added Dess-Martin Periodinane (206 mg, 0.49 mmol). The reaction mixture turned to an orange color within 3 min. After 30 min, TLC (95:5 dichloromethane/methanol) showed approximately 15% of the starting material remained. More Dess-Martin Periodinane (50 mg, 0.12 mmol) was added and the reaction was stirred for and additional 30 min. The curde product was purified on 10 g silica eluting with 0 to 3% methanol/dichloromethane to give a clear film. The material was further purified on reverse phase high performance chromatography eluting with water/acetonitrile (0.1% TFA) gradient. The final material was lyophilized from 50% acetonitrile/water to give a pale yellow powder. M+1=461.3. NMR (CD3CN/D2O 3:1) s (3H; 3.5 ppm), s (2H; 3.8 ppm), s (2H; 4.3 ppm), dd (2H; 7.15 ppm), m (4H, 7.2-7.3 ppm), m (3H, 7.45-7.55 ppm), d (2H, 7.62 ppm), d (1H, 7.72 ppm), d (1H, 7.84 ppm), d (1H, 7.88 ppm), d (2H, 8.39 ppm). M+1=461.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[CH2:40]([Sn](CCCC)(CCCC)CCCC)[CH:41]=[CH2:42]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2)[CH:41]=[CH2:40]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Br)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A reaction vial was charged with 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (EXAMPLE 53, Step 1; 0.347 g, 0.542 mmol) and Pd(PPh3)4 (0.031 g, 0.027 mmol), and then diluted with DMF (1.084 ml). After purging with nitrogen, allyltributyltin (0.202 ml, 0.650 mmol) was added and the reaction was heated to 100° C. for 30 minutes until completion. The reaction was concentrated in vacuo and purified via silica-gel chromatography (12-g RediSep Gold column), eluting with 0-30% ethyl acetate in heptanes) to yield 4-(2-allyl-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.312 g, 0.519 mmol, 96% yield) as a yellow oil. m/z (ESI) 602.1 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:14][C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1>>[CH2:24]([O:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[CH2:15][OH:14])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)c1cc(F)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc(F)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
LAH (226 mg, 5.95 mmol) was added to a solution of 2-benzyloxy-5-fluoro-benzoic acid benzyl ester (2 g, 5.95 mmol) at 0° C. The reaction was warmed to room temperature and after 1 hour, the reaction was quenched by the sequential addition of water (226 μL), 15% NaOH (226 μL), and water (760 μL), the mixture was diluted with ethyl acetate and dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to afford 1.13 g (82%) of the title compound as a colorless solid. MS 250 (M+NH4)+. 1H NMR (400 MHz, CDCl3) δ 7.4 (m, 5H); 7.05 (dd, 1H, J=9.1, 4.3 Hz); 6.92 (m, 2H); 5.08 (s, 2H); 4.65 (s, 2H); 2.2 (bs, 1H).
Reaction SMILES: [NH2:1][S:2]([CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:3])=[O:4])=[O:29])[N:22]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CN(C)C(=O)c1ccccc1CS(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2C(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 0.48 g of the compound of Example 18 and 0.54 g of N-(4,6-dimethoxypyrimidin-2-yl)carbamic acid, phenyl ester in 25 ml of acetonitrile was added 0.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was stirred overnight at room temperature. Ice (25.0 g) was added; the aqueous mixture acidified with concentrated hydrochloric acid and then extracted with two 75 ml portions of methylene chloride. The organic solution was washed with water, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Trituration of the oily residue with 1-chlorobutane gave 0.42 g of 2-[[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl]-N,N-dimethylbenzamide, m.p. 141°-143°; IR (nujol): 1700 and 1600 cm-1 ; NMR (CDCl3): δ 2.93-3.13 (6H, N(CH3)2, 2 singlets), 3.83 (6H, OCH3, s), 5.0 (2H, CH2, s) and 5.76 (1H, CH, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][C:31]([C:33](=O)[CH3:34])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:14]1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:33]([C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[O:21])=[CH:27][CH:26]=2)=[CH:29][CH:30]=1)[CH3:34]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=C1C(=O)Nc2ccc(Cl)cc21)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Yield: 19.4 %

Procedure:
A solution of 5-chlorooxindole (362 mg, 2.17 mmol), 1-(5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethanone (800 mg of oil) and piperidine (214 μL, 2.17 mmol) in toluene (10 mL) was heated at reflux with a Dean-Stark receiver for 16 hours. After evaporation of the solvent, purification by silica column chromatography (methanol gradient in dichloromethane, 0 to 5% vol) gave 5-chloro-3-(1-(5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethylidene)indolin-2-one (200 mg) as an E:Z mixture. LCMS (ES): m/z 476 [M+1]+.
Reaction SMILES: N1(C(N2C=CN=C2)=O)C=CN=C1.NC1C2C(=NC=C(Br)C=2N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)NC=1.N1CCC1.[Br:42][C:43]1[C:44]([N:60]2[CH2:65][CH2:64][CH2:63][C@@H:62]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:61]2)=[C:45]2[C:51]([NH:52][C:53]([N:55]3[CH:59]=[CH:58]N=[CH:56]3)=[O:54])=[CH:50][NH:49][C:46]2=[N:47][CH:48]=1>C1COCC1>[N:55]1([C:53]([NH:52][C:51]2[C:45]3[C:46](=[N:47][CH:48]=[C:43]([Br:42])[C:44]=3[N:60]3[CH2:65][CH2:64][CH2:63][C@@H:62]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:71])([CH3:70])[CH3:72])[CH2:61]3)[NH:49][CH:50]=2)=[O:54])[CH2:59][CH2:58][CH2:56]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)n4ccnc4)c23)C1
Agent: C1CNC1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)N4CCC4)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
Di(1H-imidazol-1-yl)methanone (3.2 g, 19 mmol) was added to (R)-tert-butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (2.0 g, 4.9 mmol; Example 98, Step A) in THF (100 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction solution was used as is. Azetidine (113 mg, 1.98 mmol) was added to (R)-tert-butyl 1-(5-bromo-3-(1H-imidazole-1-carboxamido)-1H-pyrrolo [2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (200 mg, 0.397 mmol) in THF (20 mL), and the reaction was stirred for 18 hours. The reaction was concentrated to dryness and then purified by reverse phase chromatography (SP4, 25M, water/ACN 90/10->0/100, 30 CV) to yield (R)-tert-butyl 1-(3-(azetidine-1-carboxamido)-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (90 mg, 46.0% yield) as a solid.
Reaction SMILES: N1C=CC=C(CN)C=1.[F:9][C:10]1[CH:11]=[C:12]([CH2:17][NH2:18])[CH:13]=[C:14]([F:16])[CH:15]=1.[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[C:26]2=[O:40])=[CH:22][CH:21]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:17][NH:18][C:37]([C:33]1[S:32][C:31]([N:27]2[CH2:28][C@@H:29]([CH3:30])[N:25]([CH2:24][C:23]3[CH:41]=[CH:42][C:20]([F:19])=[CH:21][CH:22]=3)[C:26]2=[O:40])=[N:35][C:34]=1[CH3:36])=[O:38]
Reactant: NCc1cc(F)cc(F)c1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc(F)cc(F)c1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3,5-difluorophenyl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 159-160° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.75 (t, J=5.6 Hz, 1H), 7.40-7.35 (m, 2H), 7.21-6.99 (m, 5H), 4.60 (d, J=15.6 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.20 (dd, J=10.1, 9.1 Hz, 1H), 3.78-3.71 (m, 1H), 3.56 (dd, J=10.2, 6.8 Hz, 1H), 2.48 (s, 3H), 1.22 (d, J=6.1 Hz, 3H); MS (ES+) m/z 474.9 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([O:34][CH3:35])(=[O:33])[CH2:31][SH:32]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)CS
Solvent: ClCCl
Product: COC(=O)CSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1 h

Procedure:
To a mixture of the alcohol (1.56 g) (Step II) and methyl thioglycolate (414 μL) in dichloromethane (20 mL) at 0° was added BF3 ·OEt2 (1.10 mL) dropwise. The mixture was stirred at 0° for 1 h and poured onto buffer (pH 7), extracted with dichloromethane and the organic phase was dried and evaporated. Flash chromatography using 20% ethyl acetate/hexane afforded the title compound as a syrup.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:23][C:9]1[N:8]([CH2:7][C:4]2[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[S:6][N:5]=2)[C:16]2[C:11]([CH:10]=1)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(Cl)n1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 327 using 1-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 326) and [3-(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 467 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of 0.72 g of 3-bromopropanol, 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of toluene, 0.06 g of tetra-n-butylammonium bromide and 5.0 g of water was added 0.77 q of a 27% aqueous sodium hydroxide solution, The mixture was heated to 60° C. and stirred for 8 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.2 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 92%, yield: 93%).
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([F:27])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3CC(C[CH:4]1[CH2:5]3)C2)#[N:2].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1)#N.CS(N)(=O)=O.[CH:56]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57]1>>[C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([NH:62][S:59]([CH:56]3[CH2:58][CH2:57]3)(=[O:61])=[O:60])=[O:21])=[C:17]([F:27])[CH:16]=2)[CH2:10][CH2:11][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCCCC1
Product: N#CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCCCC1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and making variations as required to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.092 g, 66% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.99 (d, J=12.8 Hz, 1H), 4.15 (s, 2H), 3.08-3.00 (m, 1H), 2.03-1.95 (m, 3H), 1.73-1.66 (m, 3H), 1.51-1.38 (m, 4H), 1.23-1.15 (m, 1H), 1.09-1.05 (m, 4H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −112.3 (s, 1F); MS (ES−) m/z 419.2 (M−1).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:25][C:26]1[CH:54]=[CH:53][C:29]([C:30]([C:32]2[N:36]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:35]3[CH:42]=[CH:43][C:44]([C:46]([N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=O)=[CH:45][C:34]=3[N:33]=2)=[O:31])=[CH:28][CH:27]=1)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]1[CH:54]=[CH:53][C:29]([C:30]([C:32]2[N:36]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:35]3[CH:42]=[CH:43][C:44]([C:46](=[S:10])[N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[CH:45][C:34]=3[N:33]=2)=[O:31])=[CH:28][CH:27]=1)[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOc1ccc(C(=O)c2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)c2nc3cc(C(=S)N(CC)CC)ccc3n2CCC(C)C)cc1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Lawesson's reagent (0.0963 g, 0.238 mmol) was added to a stirred solution of 2-(4-ethoxybenzoyl)-N,N-diethyl-1-isopentyl-1H-benzimidazole-5-carboxamide (0.0451 g, 0.104 mmol) in dry toluene (5 mL) under an atmosphere of N2. The reaction was heated to reflux for 0.5 h, and then cooled to room temperature and concentrated. The residue was purified by column chromatography (3:1 Hexanes:EtOAc) to provide the title compound (0.0137 g, 29%) as a glassy yellow solid. 1H-NMR (CD3OD): δ 8.19 (d, J=9.2 Hz, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.06 (d, J=9.2 Hz, 21), 4.55 (dd, J=8.4 Hz, J=7.2 Hz, 2H), 4.17 (q, J=7.6 Hz, 4H), 3.53 (q, J=7.6 Hz, 2H), 1.80–1.71 (m, 2H), 1.71–1.58 (m, 1H), 1.44 (t, J=7.6 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.17 (t, J=7.6 Hz, 3H), 0.97 (d, J=6.4 Hz, 6H). 13C-NMR (CD3OD): δ 201.23, 185.95, 165.57, 149.55, 141.87, 141.18, 136.28, 134.64, 130.31, 124.56, 118.20, 115.41, 112.36, 65.15, 47.48, 44.89, 40.18, 27.20, 22.77, 14.95, 14.07, 11.44. MS (ESI) (M+H)+=452. Anal. Calcd for C26H33N3O2S.0.3H2O: C, 68.33; H, 7.41; N, 9.19. Found: C, 68.44; H, 7.52; N, 9.01.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:17]([C:19]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[O:20])[N:18]=2)=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+]>>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[C:17]([C:19]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[O:20])[N:18]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc(OCCOC(C)=O)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2[nH]c(-c3ccc(OCCO)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-(2-Acetoxyethyloxy)phenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide is hydrolyzed with sodium hydroxide to give 2-(4-(2-hydroxyethyloxy)phenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:21]2[CH:20]([CH3:22])[CH2:19][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][C:16]=2[CH:15]=[C:14]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:40]=[O:41]>>[CH2:6]([N:13]1[C:21]2[CH:20]([CH3:22])[CH2:19][N:18]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][C:16]=2[C:15]([CH:40]=[O:41])=[C:14]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1CN(Cc2ccccc2)Cc2cc(-c3ccccc3)n(Cc3ccccc3)c21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CN(Cc2ccccc2)Cc2c(C=O)c(-c3ccccc3)n(Cc3ccccc3)c21
Temperature: 50 °C

Procedure:
Phosphoryl chloride (1.68 g) was added dropwise to cooled dimethyl-formamide (1.60 g). A suspension of 1,5-dibenzyl-4,5,6,7-tetrahydro-7-methyl-2-phenyl-1H-pyrrolo[3,2-c]pyridine (3.92 g) in dimethylformamide (20 ml) was added portionwise. The resulting red solution was heated at 50° C for 4 hours, allowed to cool and poured on to 250 g ice. The mixture was basified with 2N sodium hydroxide, warmed gently for a few minutes, and the solid product collected by filtration, washed with water and dried. Two recrystallisations from methanol gave 2.86 g of the title compound as white needles. M.pt. 120°-1°. (Found: C, 83.2; H, 6.9; N, 6.5. C29H28N2O requires: C, 82.8; H, 6.7; N, 6.7%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][NH2:43])[CH:38]=[CH:39][CH:40]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:15]([CH3:18])(=[O:16])=[O:17])=[N:27][C:28]([NH:43][CH2:42][CH2:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[N:29][CH:30]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3cccc(F)c3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 502. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H), 8.19 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.08 (m, 3H), 6.87 (m, 1H), 4.55 (s, 2H), 3.91 (m, 1H), 3.64 (t, 2H), 3.34 (m, 2H), 3.03 (s, 3H), 3.00 (m, 2H), 2.92 (t, 2H), 1.91 (m, 4H).