Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=1
Reactant: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCC(=O)Nc1ccc(N)cc1

Procedure:
A solution of 4'-nitrovaleranilide (13.33 g., 0.06 mole) in absolute ethanol (750 ml.) is hydrogenated over 10% palladium on charcoal (2 g.) until the theoretical absorption is achieved. The catalyst is removed and the solvent is removed in vacuo. The residue is recrystallized from butyl chloride to yield 9.0 g., m.p. 81°-83° C.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:39][C:38]3=[O:51])=[N:32][CH:33]=1)([O-])=O>>[NH2:25][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:39][C:38]3=[O:51])=[N:32][CH:33]=1
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)C(=O)CC(c2ccccc2)O3)nc1

Procedure:
6-(5-Aminopyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 100 mg of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one (Example 6). 1H NMR (400 MHz, CD3OD) δ: 7.62 (d, 1H, J 3.0 Hz), 7.51-7.49 (m, 2H), 7.42-7.33 (m, 3H), 7.25-7.18 (m, 3H), 7.06 (d, 1H, J 8.8 Hz), 6.76 (d, 1H, J 8.6Hz), 5.50 (dd, 1H, J 13.0, 2.9 Hz), 3.08 (dd, 1H, −17.0, 13.0 Hz), 2.82 (dd, 1H, J −17.0, 2.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][CH:32]1[CH2:36][CH2:35][CH:34]([CH3:37])[NH:33]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH:34]([CH3:37])[CH2:35][CH2:36][CH:32]4[CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1CCC(C)N1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1C(C)CCC1C

Procedure:
In the same manner as Example 117, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide. (0.51 mmol.) was reacted with 2,5-dimethylpyrrolidine (1.02 mmol., 101 mg.) in dimethylformamide. The crude product was also purified via chromatography as Example 117, leaving 214 mg. (82%) of the yellow product: mp 110-113° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=O)C(F)(F)F)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].[OH-].[K+].CI>CC(C)=O>[CH3:19][NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:6]2[N:5]=[C:4]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:3]([C:1]#[N:2])=[C:7]2[N:8]=[CH:9][CH:10]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3ccccc3NC(=O)C(F)(F)F)ccnc12
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: CNc1ccccc1-c1ccnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn12
Reaction time: 15 h
Yield: 35.9 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (50 mg, 0.1 mmol) in 5 mL of acetone was added KOH (11.2 mg, 0.2 mmol) and CH3I (0.5 mL). The reaction mixture was stirred at It for 15 hr, then concentrated to remove acetone. The residue was partitioned between 20 mL of water and 20 mL of EA. The organic layer was concentrated and purified by pre-TLC (PE/EA=2/1) to give the product as a white solid (15 mg, yield: 37%). 1H NMR (DMSO-d6) δ 8.82 (d, J=4.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.47-7.38 (m, 4H), 7.31 (dd, J=1.6, 7.2 Hz, 1H), 7.23-7.17 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.77-6.69 (m, 2H), 5.35-5.31 (m, 1H), 2.68 (d, J=4.8 Hz, 3H). MS (ESI) m/e [M+1]+ 417.9.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.[C-]#N.[Na+]>CN(C)C=O.O>[CH:1]1([O:6][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccsc1
Reactant: OC1CCCC1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC2CCCC2)cs1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a solution of cyclopentanol (8.75 ml, 95.8 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (60% dispersion in mineral oil, 3.84 g, 95.8 mmol) at 0–5° C. under nitrogen. After 10 minutes, the mixture was allowed to reach room temperature and stirred for 40 minutes. 3-Bromothiophene (3.59 mL, 38.3 mmol) was added followed by cuprous iodide (14.63 g, 76.8 mmol). The mixture was heated at 120° C. for 22 hours. After cooling to about 10° C., a solution of sodium cyanide (12.1 g, 0.25 mol) in water (200 mL) was added under vigorous stirring. The mixture was stirred for additional 10 minutes then filtered. The filtrate was extracted with hexane. The extract was washed with water, dried (Na2SO4) and concentrated to dryness. Distillation (100° C., 8 mm Hg) gave 3-cyclopentyloxythiopene (4.52 g, 70%) as a slightly pale yellow oil; 1H NMR (300 Mz, CDCl3) δ 7.15 (dd, J=5.2, 3.1 Hz, 1H), 6.72 (dd, J=5.2, 15 Hz, 1H) 6.19 (dd, J=3.1, 1.5 Hz, 1H), 4.65 (quintet, J=4.2 Hz, 1H), 1.55–1.95 (m, 8H). MS m/e (%): 168 (M+; 17).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.O[Li].O.Cl>C1COCC1.C(Cl)Cl.CO>[CH3:37][C:33]1([CH3:36])[CH2:34][CH2:35][C:30]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:21]3)[C:11]([C@H:13]3[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[CH:8]=2)=[CH:31][CH2:32]1
Reactant: COCO[C@H]1CC[C@H](N(c2cc(C3=CCC(C)(C)CC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCC(C)(C)CC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
The methyl ester from Step I (285 mg, 0.54 mmol) was dissolved in a 4:2:1 mixture of THF:H2O:methanol (7 mL), LiOH.H2O (225 mg, 5.36 mmol) was added to solution, and it was heated in a microwave oven at 120° C. for 5 min, then for an additional 5 min at 130° C. The reaction mixture was diluted with CH2Cl2, acidified with 2N HCl, washed with brine, and organic fraction was dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silicagel eluting with 0-10% MeOH in CH2Cl2 to give 265 mg (95%) of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F:26][C:27]([F:56])([F:55])[C:28]1[CH:29]=[C:30]([C:38]2[C:39]3[N:40]([N:44]=[C:45]([NH:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH:49]4[F:54])[N:46]=3)[CH:41]=[CH:42][CH:43]=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.Cl[C:58]1[S:62][N:61]=[C:60]([CH3:63])[N:59]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][C:27]([F:26])([F:55])[C:28]1[CH:29]=[C:30]([C:38]2[C:39]3[N:40]([N:44]=[C:45]([NH:47][CH:48]4[CH2:53][CH2:52][N:51]([C:58]5[S:62][N:61]=[C:60]([CH3:63])[N:59]=5)[CH2:50][CH:49]4[F:54])[N:46]=3)[CH:41]=[CH:42][CH:43]=2)[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1
Reactant: FC1CNCCC1Nc1nc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccn2n1
Reactant: Cc1nsc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cccn4n3)C(F)C2)n1
Temperature: 150 °C

Procedure:
A degassed solution of palladium(II) acetate (2.73 mg, 12.2 μmol) and 2-(dicyclohexylphosphino)biphenyl (8.52 mg, 24.3 μmol) in dioxane (1 mL) was stirred for 10 minutes at room temperature, then added to a solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (68 mg, 152 μmol), 5-chloro-3-methyl-1,2,4-thiadiazole (24.5 mg, 182 μmol) and sodium tert-butoxide (21.9 mg, 228 μmol) in dioxane (2 mL). Through the solution was bubbled argon for 5 minutes, then heated to 150° C. in the microwave for 45 minutes. Again a degassed solution of palladium(II) acetate (3.1 mg, 13.8 mmol) and 2-(dicyclohexylphosphino)biphenyl (9.69 mg, 27.6 μmol) in dioxane (1 mL) was added, followed by 5-chloro-3-methyl-1,2,4-thiadiazole (24.5 mg, 182 μmol) and heated for further 45 minutes to 150° C. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as colorless oil (30 mg, 36%) as a mixture of cis- and trans-isomers.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:6]=1[C:7](=[NH:8])[O:18][CH2:16][CH3:17])[CH3:3]
Reactant: CCOc1ccc(C#N)c(OCC)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OCC)cc1OCC
Temperature: 25 °C
Reaction time: 288 h
Yield: 95 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2,4-diethoxybenzonitrile (1.86 g, 9.7 mmol) in absolute ethanol (20 mL) in a pressure tube for 1 h at −10° C. The tube was sealed and stirred at room temperature for 12 d. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 2,4-diethoxy-benzimidate hydrochloride (2.53 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)Cl.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Br)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(Br)cc1

Procedure:
prepared by reaction of 3-(4-bromo-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=312.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([O:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:24]2=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C1C=CC(=O)N1C1CCCCC1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1C1CCCCC1
Yield: 61.1 %

Procedure:
The procedure of Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 4.48 g (25 mmole) of N-cyclohexylmaleimide. The residue was crystallized from ethanol to give 6.0 g (61%) of a white solid, mp 75°-77° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.C(OC)(=O)[CH2:14][C:15](OC)=[O:16].[H-].[Na+]>[Fe]>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2]([CH2:14][C:15](=[O:16])[NH:10]2)=[CH:7][CH:6]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)NC(=O)C2
Yield: 18.4 %

Procedure:
In a manner similar to the method described in example 167a, 1-chloro-4-methoxy-2-nitro-benzene (19 g, 0.1 mol) was reacted with dimethyl malonate (16 g, 0.2 mol), NaH and iron power to give 6-methoxy-1,3-dihydro-indol-2-one (3 g, 18%).
Reaction SMILES: [CH2:1]([C:6]1(C(OCC=C)=O)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[C:2]#[C:3][CH2:4][CH3:5].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: C=CCOC(=O)C1(CC#CCC)CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCC#CCC1=CCCC1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A vessel was charged with 1 mole of allyl 1-(2-pentynyl)-2-oxocyclopentanecarboxylate of the following formula ##STR5## 20 moles of acetonitrile and 0.01 mole of palladium acetate. At room temperature, they were rapidly stirred. The mixture was then heated to the boiling point of the solvent, and the reaction was carried out under reflux for 30 minutes. After the reaction, the reaction mixture was distilled under reduced pressure in a customary manner to give 2-(2-pentynyl)-2-cyclopenten-1-one (PCP for short) in a yield of 85%. This compound was identified by using its IR, NMR and mass spectra.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:21](O)=[O:22])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH2:38]([CH2:40][NH2:41])[OH:39].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[N:4]=[C:5]([C:21]([NH:41][CH2:40][CH2:38][OH:39])=[O:22])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2]
Reactant: COc1ccc2c(C(=O)O)nc(C#N)c(-c3ccccc3)c2c1
Reactant: NCCO
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)NCCO)nc(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMF was added to a vial containing 3-cyano-6-methoxy-4-phenylisoquinoline-1-carboxylic acid (0.072 g, 0.237 mmol), EDC (0.068 g, 0.355 mmol) and HOAt (0.048 g, 0.355 mmol). Ethanolamine (0.029 g, 0.473 mmol) and DIEA (0.153 g, 1.183 mmol) were added to this mixture, and the reaction stirred at rt overnight. The reaction mixture was filtered and purified by r.p. HPLC. White solid (0.038 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:3]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)n[nH]1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(N)cc2)n[nH]1

Procedure:
The 5-methyl-N-(4-nitrophenyl)-1H-pyrazol-3-amine (1) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][C:35]([O:37]C)=[O:36])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:39]4[CH2:41][CH2:40]4)[N:21]=3)[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>CO>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][C:35]([OH:37])=[O:36])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:39]4[CH2:40][CH2:41]4)[N:21]=3)[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C3CC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C2CC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl {3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-cyclopropylpyridin-3-yl]-4-methoxyphenyl}acetate (43 mg, 0.069 mmol) in MeOH (4 mL) was added 4M KOH (200 μL, 0.8 mmol). The reaction was stirred at room temperature for 4 hours and then quenched with HOAc (75 μL), diluted with EtOAc (30 μL), and washed with water and brine (10 mL each). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 100% EtOAc/hexanes) afforded {3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-cyclopropylpyridin-3-yl]-4-methoxyphenyl}acetic acid. LCMS=609.4 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.84 (s, 1H), 7.72 (s, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.27 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.07 (bs, 1H), 6.93 (d, J=8.5 Hz, 1H), 5.53 (bs, 1H), 4.85 (d, J=16.0 Hz, 1H), 3.86-4.20 (m, 2H), 3.78 (s, 3H), 3.61 (s, 2H), 2.07 (m, 1H), 1.00-1.10 (m, 4H), 0.54-0.70 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[OH:12]S(O)(=O)=O>>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[N:5]=[C:4]2[S:11][N:2]=[C:1]([OH:12])[C:3]=12
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)c(C#N)c(S)n1
Product: Cc1cc(C)c2c(O)nsc2n1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
3-Cyano-4,6-dimethyl-2-mercaptopyridine (4.7 g, 28.6 mmol) is dissolved in H2SO4(60 ml, 98%) and then stirred at 105° C. for 3 h. The reaction is monitored by HPLC-MS. The reaction solution is cooled to 25° C. and then poured onto ice. The product eventually (15 min) precipitates out as a voluminous solid and is filtered off with suction and washed with H2O. The residue is taken up with aqueous Na2CO3 solution (pH 8-9) and the product is extracted with EtOAc. The solvent is distilled off under reduced pressure and the residue (white solid) is dried (Na2SO4).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH:24]=[N+:25]([CH3:27])[CH3:26].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]([N:25]([CH3:27])[CH3:26])[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccc(OC)c(OC)c2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([C:19](O)=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][O:15][C:11]=3[C:10]=2[F:22])=[C:4]([Cl:23])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([C:19]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][O:15][C:11]=3[C:10]=2[F:22])=[C:4]([Cl:23])[CH:3]=1
Reactant: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NS(C)(=O)=O)cc12
Temperature: 50 °C
Yield: 69.9 %

Procedure:
A mixture of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (9a) (41 mg, 0.102 mmol) and carbonyldiimidazole (23 mg, 0.140 mmol) in THF (1 mL) was stirred at 50° C. in a sealed tube reactor. The reaction mixture was cooled to room temperature and methanesulfonamide (17 mg, 0.179 mmol) was added followed by DBU (0.025 mL, 0.164 mmol). After stirring at 50° C. for 1 hour, the reaction mixture was cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water, 1 N HCl, and brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (7% MeOH in CH2Cl2) provided 34 mg (65% yield) of the desired product (13a). MS APCI (−) m/z 474, 476 (M+, Br, Cl pattern) detected. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.53 (s, 1H), 7.27 (d, 1H), 6.73 (t, 1H), 3.11 (s, 3H), 2.55 (s, 3H): 19F NMR (376 MHz, CD3OD)−141.84 (s, 1F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([O:14]C2CCCCO2)[CH3:13])[CH2:11][O:10]1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
2-(2,4-Difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane (82 g) (sythesized by a method disclosed in the Japanese Laid-Open Publication Hei-04/74168) and 6.3 g of pyridinium p-toluenesulfonte were dissolved in 600 ml of ethanol and the solution was stirred at 55° C. for one hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in one liter of ethyl acetate and the resulting solution was washed with water (2×200 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=10/1 to 8/1 to 3/1) to give 31.5 g of (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][NH2:35])[N:30]=[CH:29]1>CO>[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][NH:35][C:15]([C:14]2[CH:20]=[CH:21][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:4]=3)=[O:10])=[CH:12][CH:13]=2)=[NH:19])[N:30]=[CH:29]1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: N=C(NCCc1c[nH]cn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2-(1H-imidazol-4-yl)ethanamine (25 mg, 0.23 mmol) via procedure W to afford 90 mg of 4-(N-(2-(1H-imidazol-4-yl)ethyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 445 (M)+.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:51])[CH:38]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.COC[CH2:55][S:56]([NH2:59])(=[O:58])=[O:57].CS(N)(=O)=O>>[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:42])=[C:39]([F:51])[CH:38]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 58 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.070 g, 58%): 1H NMR (300 MHz, DMSO-d6) δ 11.93 (br s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.00 (d, J=13.0 Hz, 1H), 3.71-3.54 (m, 2H), 3.31 (s, 3H), 2.85-2.71 (m, 1H), 2.03-1.87 (m, 5H), 1.75-0.155 (m, 12H); MS (ES+) m/z 458.1 (M+1).