Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1C[CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10]C1)=O)(C)(C)C.C1(CN2C(=O)C(C[O:46][S:47]([CH3:50])(=O)=[O:48])=CC(C3C=CC(S(C)(=O)=O)=CC=3)=N2)CC1.CNC>>[CH:30]1([CH2:29][N:16]2[C:15](=[O:33])[C:14]([N:11]([CH3:10])[CH3:12])=[C:19]([CH3:20])[C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:47]([CH3:50])(=[O:48])=[O:46])=[CH:25][CH:26]=3)=[N:17]2)[CH2:31][CH2:32]1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CNC
Product: Cc1c(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c(=O)c1N(C)C
Yield: 65.6 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 65.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCCCO)cc1
Reaction time: 20 h
Yield: 89 %

Procedure:
To a stirring solution of 4-(4-hydroxy-but-1-ynyl)-benzoic acid methyl ester (6.29 g, 0.031 mol) in ethanol (60 mL) was added palladium on carbon (5 g, 10% on carbon) and the reaction mixture was hydrogenated at 50 psi. After 20 hours, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to afford 4-(4-hydroxy-butyl)-benzoic acid methyl ester (5.67 g, 0.027 mol) as the desired product (89% yield). 1H (CDCl3, 600 MHz): δ 7.94 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 3.89 (s, 3H), 3.65 (2H, t, J=6.6 Hz), 2.65 (2H, t, J=7.8 Hz), 1.71 (2H, m), 1.58 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:10](=[O:13])[N:11]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)=[O:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(F)c2)c1=O)NCc1cccc(C(F)(F)F)c1

Procedure:
200 mg (0.66 mmol) of 5-(4-chlorophenyl)-4-(3-fluorophenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 41A, 193 mg (0.69 mmol) of 2-chloro-N-[3-(trifluoromethyl)phenylmethyl]-acetamide [preparable according to EP 0 163 607, Example 28] and 182 mg (1.32 mmol) of potassium carbonate are suspended in 2.5 ml of acetonitrile and heated under reflux overnight. After cooling, this is diluted with water, and purified by preparative HPLC [Method 9] and 219 mg (64% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19](Cl)(=[O:21])=[O:20])=[C:10]2[O:15]C(=O)C)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(=O)([O-])[O-].[NH4+:31].[NH4+].Cl>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([NH2:31])(=[O:21])=[O:20])=[C:10]2[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc2c(O)c(S(N)(=O)=O)ccc12

Procedure:
The 5-acetamido-1-hydroxynaphthalene-2-sulfonamide was prepared by dissolving 10.8 g. of 5-acetamido-1-acetoxynaphthalene-2-sulfonyl chloride in 10 ml. dry chloroform and heating on the steam bath with 25.0 g. anhydrous ammonium carbonate for 2.5 hours. The yellow-brown solid was dissolved by heating with 50 ml. water on the steam bath for 4 hours. Acidification with dilute hydrochloric acid to pH 5 caused the sulfonamide to precipitate. It was filtered off, washed and dried, yielding 5.61 g. (63%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[CH:9]=[N:10][NH:11][C:4]=2[CH:3]=1.[OH-].[K+].[I:14]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:14])=[N:10][NH:11][C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2[nH]ncc12
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)cc2[nH]nc(I)c12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A 100 mL round bottom flask was charged with 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridine (1.20 g, 7.16 mmol) and DMF (28.5 mL). The reaction flask was warmed to 70° C. and KOH (1.2 g, 21.48 mmol) was added. Iodine (5.45 g, 21.48 mmol) was added gradually over 1 h. The reaction mixture was stirred for 3 h then additional KOH (3.2 g, 57.0 mmol) and iodine (15.6 g, 61.5 mmol) were added. The reaction was heated at 70° C. for 2 h. The reaction was poured into saturated sodium thiosulfate (500 mL) and diluted with EtOAc (200 mL). The aqueous phase was extracted with EtOAc (200 mL, ×2). The combined organic phase was washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 6-chloro-3-iodo-4-methyl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C7H5ClIN3 [M+1]+ 294. found 294.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Na+].[I-:13]>CN(C=O)C.Cl>[I:13][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
4-(trifluoromethyl)-phenol (8 g) in anhydrous DMF (80 ml) was cooled to 0° C. NaI (9.06 g) and chloroamine-T (16.1 g) was added portionwise and stirred at room temperature overnight. Then diluted with 2M HCl and extracted with ethylacetate. The organic phase was washed with sodium thiosulfate solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (silica, eluting with isohexane:ethyl acetate) to give the sub-title compound as a yellow oil (13 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8][C:9]2SC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.C(N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:9]([NH:8][C:5]1[N:4]=[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:35])([CH3:36])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])[C:2]([Cl:1])=[CH:7][N:6]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)s2)ncc1Cl
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2ccccc2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with benzylamine.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:17])[C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.FC(F)C1N(C)N=CC=1.O>CN(C)C=O>[Br:1][C:15]1[C:11]([CH:10]([F:17])[F:9])=[N:12][N:13]([CH3:16])[CH:14]=1
Reactant: Cn1ccc(C(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cn1nccc1C(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
At from 3 to 5° C., a solution of N-bromosuccinimide (NBS, 54 g, 0.3 mol) in dimethyl-formamide (DMF, 100 ml) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (49.3 g, 0.3 mol; 81.4% pure according to GC analysis) comprising, as minor component, 5.2% of 5-difluoromethyl-N-methylpyrazole, based on the total amount of the isomer mixture, in DMF (100 ml). The reaction mixture was then warmed to room temperature and stirred for a further 12 h. With stirring, the reaction mixture was then poured into water (1000 ml) and extracted twice with methyl tert-butyl ether (MTBE, 300 ml). The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and then freed from the solvent under reduced pressure. 4-Bromo-3-difluoromethyl-N-methylpyrazole was obtained as an oil (76.6 g; purity: 74.2% according to GC analysis) comprising 4.5% of unreacted 5-difluoromethyl-N-methylpyrazole. This corresponds to a yield of 89%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CO.C(Cl)Cl.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[O:13])[CH2:9]3)=[CH:4][CH:3]=2)[CH2:27]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: O=C(C1CCOCC1)N1CCc2ccc(Br)cc2C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CN(C(=O)C2CCOCC2)CC3)C1
Temperature: 85 °C
Yield: 52.8 %

Procedure:
A vial was charged with (7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(tetrahydro-pyran-4-yl)-methanone (162 mg, 0.5 mmol), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl (90 mg, 0.55 mmol), and sodium tert-butoxide (69 mg, 0.7 mmol), tris(dibenzylideneacetone)dipalladium-(0) (4.6 mg, 0.005 mmol), BINAP (9.3 mg, 0.015 mmol), and toluene (4 mL) under argon. The vial was capped with a septum and was heated to 85° C. (external) with stirring until the starting material was completely consumed as monitored by TLC analysis. The mixture was allowed to cool to room temperature, taken up in ether (5.0 mL), filtered, and concentrated. The crude product was then purified further by flash chromatography on silica gel, eluted with 3% MeOH in DCM and 7.5% MeOH in DCM to 105 mg (53% yield) of the title compound as a tan solid.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].ClC(Cl)(Cl)C(O[CH:26]([CH3:28])[CH3:27])=N.COCCOC.FC(F)(F)S(O)(=O)=O>CCCCCCC>[C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([O:20][CH:26]([CH3:28])[CH3:27])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](O)Cc1cccc(OC(=O)C(C)(C)C)c1
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1cccc(OC(=O)C(C)(C)C)c1)OC(C)C
Yield: 95.6 %

Procedure:
Methyl (2S)-3-(3-pivaloyloxyphenyl)-2-hydroxypropionate (11 kg), 2,2,2-trichloro-1-isopropoxyethanimine (20 kg, 98 mol), 1,2-dimethoxyethane (10 L), and heptane (44 L) were mixed and stirred, and the resultant solution was cooled to 7° C. Trifluoromethanesulfonic acid (2.36 kg, 15.7 mol) was added dropwise to the reaction mixture over a period of 36 minutes, followed by stirring the reaction mixture at 25° C. for 19 hours. The reaction mixture was cooled to 7° C., to which heptane (66 L) was then added. The reaction mixture was then stirred for 45 minutes, followed by filtering off a white crystal of trichloroacetoamide. Water (55 L) was added to the filtrate for separating. Then, the organic layer was washed with a 5% sodium bicarbonate aqueous solution (52 L) twice and with water (55 L), followed by vacuum concentration to obtain 12.1 kg of the title compound (yield: 96%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl
Product: CCOC(=O)c1csc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 320 from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (intermediate 1) and ethyl 2-bromo-1,3-thiazole-4-carboxylate (commercially available).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:31](=[O:32])[NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:34])[F:33])[CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (256 mg, 1.23 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.19 ml, 1.4 mmol) and α,α,α-trifluoro-m-tolyl isocyanate (345 μl, 2.46 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 180 mg (37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)C(=O)c1cccc(Br)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc(Br)c1
Yield: 37.8 %

Procedure:
Compound 4d was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-bromophenyl)-2-hydroxypropan-1-one (10d, 4.0 g, 0.018 mol), Proton sponge (4.5 g, 0.021 mol), triflic anhydride (3.2 mL, 192 mmol), and 2-amino-2-methyl-1-propanol (3.4 g, 0.038 mol) in acetonitrile (50 mL). After purification, 2.04 g (39%) of the free base 4d was isolated and converted to 1.6 g of the hemi-D-tartrate salt, which had >99% ee: mp 129-130° C.; [α]20D +9.6° (c 1.0, CH3OH); 1H NMR (methanol-d4) δ 7.77-7.76 (m, 1H), 7.63-7.53 (m, 2H), 7.38-7.32 (m, 1H), 4.37 (s, 1H), 4.14 (d, 1H, J=12.0 Hz), 3.58-3.39 (m, 2H), 1.57 (s, 3H), 1.32 (s, 3H), 1.07-1.02 (m, 3H); 13C NMR (methanol-d4) δ 178.8, 145.1, 133.3, 131.1, 126.9, 123.6, 96.7, 75.2, 67.7, 55.0, 24.4, 21.5, 14.4; LCMS (ESI) m/z 300.6 [(M-tartrate)+, M=C15H21BrNO5]; Anal. (C15H21BrNO5.0.25H2O) calcd: C, 47.44; H 5.71; N, 3.69. found: C, 47.33; H, 5.84; N, 3.63.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].BrC[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[I:37]>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:28]=3[I:37])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(I)c(CCBr)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1,28 mmol) as described in Example 66 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.06 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.82 (s, 2H), 7.61 (s, 1H), 7.33 (dd, J=8.2, 1.4 Hz, 1H), 5.79 (d, J=7.8 hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.40 (d, J=16 Hz, 1H), 4.16-4.06 (m, 1H), 0.83 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[C:48]([NH:87][C:88](=[O:94])[O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[N:49][CH:50]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[C:63]([CH3:76])=[N:64][N:65]([CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=5)[C:66]=4[CH3:67])=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:52]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[C:48]([NH:87][C:88](=[O:94])[O:89][C:90]([CH3:92])([CH3:91])[CH3:93])=[N:49][CH:50]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[C:63]([CH3:76])=[N:64][N:65]([CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=5)[C:66]=4[CH3:67])=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cnc(NC(=O)OC(C)(C)C)c(F)c3)cc12
Yield: 91.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl (3-fluoro-5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)carbamate (110 mg, 0.16 mmol) was hydrolyzed by lithium hydroxide (33 mg, 0.8 mmol) in THF/methanol/water (5/5/2 mL) to yield 78 mg (91.5% yield) of the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:20](O)[C:21]#[N:22])[CH2:19][CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15]>C1(C)C=CC=CC=1.O.CCOCC>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:20]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)[C:21]#[N:22])[CH2:19][CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC1CCNCC1
Reactant: N#CC(O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCN(C(C#N)C2(c3ccc(Cl)c(Cl)c3)CCC2)CC1

Procedure:
4-Methylpiperidine (4.8 g) was added to a solution of 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-hydroxyacetonitrile (12 g) in toluene (50 ml). The reaction mixture was stirred and heated at 100°-105° C. for two hours, cooled and diluted with water (100 ml) and ether (60 ml). The organic layer was separated washed with water and dried. Evaporation of the solvents gave an oil which solidified on standing to give a solid which was triturated with petroleum ether (b.p. 60°-80° C.) to give 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(4-methylpiperidino)acetonitrile (m.p. 76°-78° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].O.C(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
In one portion, 96 g (0.75 mole) of 4-chlorophenol was added to a stirred solution of 67.5 ml (0.75 mole) of chlorosulfonylisocyanate in 400 ml of toluene. The solution was heated at 100° C. for 16 hr and the solution chilled with an ice-acetone bath and water added dropwise until evolution of carbon dioxide ceased. The tan solid which precipitated from solution was collected and dried for 16 hr to yield 133.4 g. A 25 g portion was recrystallized from 100 ml of toluene to give 15.8 g of white solid, mp 103°-104° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[C:14]([O:20][CH3:21])[CH:13]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=2[O:20][CH3:21])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: COc1cc(F)ccc1[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(F)ccc1C(O)c1cccc(Br)c1F
Reaction time: 0.83 h
Yield: 82 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.5 g, 7.39 mmol) in THF (Volume: 32.1 ml) cooled to 0° C. was added (4-fluoro-2-methoxyphenyl) magnesium bromide (17.73 ml, 8.87 mmol). After 50 min, additional (4-fluoro-2-methoxyphenyl)magnesium bromide (17.73 ml, 8.87 mmol) was added. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 30 min, tr=17 min) gave the title compound (2.10 g, 6.06 mmol, 82% yield) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[OH-].[Na+]>O.C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1ccc(-c2cccs2)cc1
Reaction time: 1 h

Procedure:
4-Chloroaniline (4.0 g, 31.4 mmol) is added to 4 ml of acetic acid and heated until all solid is dissolved. The solution is cooled to 5° and 5.2 ml of conc. HCl is added, followed by the dropwise addition of sodium nitrite (2.16 g, 31.4 mmol) in 32 ml of water. After addition is complete, the mixture is stirred at 5° for 1 hour. Thiophene (2.64 g, 2.5 ml, 31.4 mmol) in 25 ml of carbon tetrachloride is added to the mixture, followed by the dropwise addition of 25% aq. NaOH (ca. 6.8 ml). After 1 hour, the mixture is poured into water and extracted with chloroform, and the combined extracts are washed with brine, dried and stripped of solvent. The black residue is distilled at ca. 120° 0.35 mm to give 2-(4-chlorophenyl)thiophene, a yellow solid.