Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:23]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:23]=2)[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccn1
Yield: 32.3 %

Procedure:
Benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (192.83 mg, 0.64 mmol) and methyl 4-chloropyridine-2-carboxylate (100 mg, 0.58 mmol) were dissolved in dioxane (3 ml) and DMF (1 mL). Palladium acetate (26.17 mg, 0.12 mmol), BINAP (145.16 mg, 0.23 mmol) and cesium carbonate (569.68 mg, 1.75 mmol) were added, and the mixture was stirred using a microwave irradiation reactor at 160° C. for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=40/1, 20/1, 10/1) to obtain 74.8 mg of the title compound as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.[C:23](Br)(=[O:25])[CH3:24]>FC(F)(F)C(O)=O>[C:23]([O:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1)(=[O:25])[CH3:24]
Reactant: COc1c(O)cc2c(c1Sc1ccccc1)CCN(C)CC2
Reactant: CC(=O)Br
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC(C)=O)cc2c(c1Sc1ccccc1)CCN(C)CC2

Procedure:
Reaction of 8-hydroxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine with acetyl bromide in trifluoroacetic acid gave 8-acetoxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine; hydrochloride salt m.p. 240°-241° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[N:27][CH:28]=1>>[CH3:29][C:26]1[N:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(O)cn1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cn1

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 5-hydroxy-2-methylpyridine using dry DME as the reaction solvent: MS (ESI) m/z 404 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2nnc(Cl)cc2N2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2nnccc2N2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
To a solution of 3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-6-chloro-pyridazin-3-yl}-azetidine-1-carboxylic acid tert-butyl ester (62) (843 mg, 1.7 mmol) in MeOH was added Pd/C (10%, 0.5 g) under nitrogen. The reaction was stirred under hydrogen at RT for 6 h, filtered to remove Pd/C and concentrated to dryness to give 3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-pyridazin-3-yl}-azetidine-1-carboxylic acid tert-butyl ester (63) (730 mg, 1.58 mmol yield 92.9%).
Reaction SMILES: ClC1C=C(CCNC(=O)C2C=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=2)C=CC=1Cl.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[C:34]([OH:36])=O.[F:44][C:45]([F:56])([F:55])[C:46]1[CH:47]=[C:48]([CH2:52][CH2:53][NH2:54])[CH:49]=[CH:50][CH:51]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[C:34]([NH:54][CH2:53][CH2:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([C:45]([F:44])([F:55])[F:56])[CH:47]=1)=[O:36]
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C(NCCc1ccc(Cl)c(Cl)c1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: O=C(NCCc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)c(Cl)c1
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to N-[2-(3,4-dichloro-phenyl)-ethyl]-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzamide (described in example S98) using 250 mg of 3-chloro-4-trifluoromethyl-benzoic acid (1.11 mmol) and 221 mg (1.17 mmol) of 2-(3-trifluoromethylphenyl)-ethylamine. The isolated residue was purified by flash column chromatography to give 360 mg of 3-chloro-4-trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (82%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1cc([N+](=O)[O-])ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 84 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.12 mmol) was converted using 2-methoxy-4-nitro-benzoic acid instead of o-toluic acid to the title compound (2.92 g, 84%) which was obtained as a white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38]S(C)(=O)=O>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Oc1ccccc1CI
Product: O=C1CN(c2ccc(Cc3ccccc3O)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methanesulfonic acid 2-iodomethylphenyl ester analogous to Example 306, steps C-F: (M−1)−=333. HPLC retention time=1.04 min (Method A).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([CH3:22])=[CH:17][CH:18]=2)[N:13]=1.[H-].[Na+].[CH3:25][CH:26]([CH3:32])[CH2:27][CH2:28][C:29](=[O:31])[CH3:30]>>[CH3:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:4]([CH2:30][C:29](=[O:31])[CH2:28][CH2:27][CH:26]([CH3:32])[CH3:25])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[N:13]2)=[CH:18][CH:17]=1
Reactant: CC(=O)CCC(C)C
Reactant: Cc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Reaction time: 2 h
Yield: 9.5 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 3-hydroxy-2-(7-methyl-1,8-naphthyridin-2-yl)-1-isoindolinone (7.9 g), an oily suspension (50% by weight; 2 g) of sodium hydride and 5-methyl-2-hexanone (6.2 g), and stirring the reaction mixture for 3 hours at a temperature in the region of -5° C., and then for 2 hours at 0° C., 2-(7-methyl-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (1 g), m.p. 155° C., is obtained after recrystallization in ethanol.
Reaction SMILES: [C:1]([N:8]([CH3:15])[C@H:9]([CH:13]=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([CH2:21][CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl.O>[C:1]([N:8]([CH3:15])[C@@H:9]([CH:10]([CH3:12])[CH3:11])/[CH:13]=[C:21](\[CH3:22])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of aldehyde 13 (1.75 g, 8.7 mmol) in dry CH2Cl2 (9.0 mL) under an argon atmosphere at room temperature was added (carbethoxyethylidene)triphenylphosphorane (4.19 g, 11.3 mmol) and stirring was continued for a 4 h. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried with magnesium sulfate and concentrated in vacuo. The crude oil was purified by flash chromatography (silica gel, 2:23 diethyl ether-pet. ether) to afford the required E-2-alkenoate 14 as a colourless oil (2.13 g, 82% yield). 1H-NMR (200 MHz, CDCl3) 0.74 (d, J=6 Hz, 3H, CH3), 0.79 (d, J=6 Hz, 3H, CH3), 1.17 (t, J=0.7 Hz, 3H, CH3), 1.34 (s, 9H, Boc-(CH3)3), 1.72 (m, 1H, CH), 1.78 (s, 3H, —CH3), 2.60 (bs, 3H, NCH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.15-4.20 (m, 0.5H, CH), 4.21-4.32 (m, 0.5H, CH), 6.54 (d, J=8 Hz, 1H, CH); Exact mass calc'd for C16H30N04 (M+H)+: 300.21750; Found (DCI): 300.21754. Optical rotation obtained was [α]D25 +61.1 (c 9.1, CHCl3).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1cccc(Cl)c1
Product: FC(F)(F)c1nnc2ccc(N3CCCN(Cc4cccc(Cl)c4)CC3)nn12

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-chlorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-chlorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C@H:8]([C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:36][S:37]SC>C1COCC1>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C@H:13]3[CH2:14][C@H:12]3[C@@H:8]([O:7][CH2:6][C:5]3[CH:29]=[CH:30][C:2]([S:37][CH3:36])=[CH:3][CH:4]=3)[CH2:9][O:10][CH3:11])[CH2:16][CH2:17]2)=[N:26][CH:25]=1)[CH3:28]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](COC)OCc3ccc(Br)cc3)CC2)nc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](COC)OCc3ccc(SC)cc3)CC2)nc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cold (−78° C.), stirred solution of the product of step G (90 mg, 0.190 mmol) in THF (1.9 mL) was added n-BuLi (0.9 mL of 2.5 M solution in hexane, 0.228 mmol). After 10 min, dimethyldisulfide (23.2 mg, 0.247 mmol) was added and the mixture stirred for 45 min at −78° C. The reaction was quenched with a saturated aqueous solution of NH4Cl, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 5:1 hexane:ethyl acetate) to yield the title compound. MS (ESI) m/z 442 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl
Yield: 18 %

Procedure:
Following the procedure of 512f, 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.091 g, 0.0005 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl benzamide (0.1 g, 0.00033 mol) were reacted. Purification by ISCO chromatography gave 2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl benzamide (0.026 g, 18%) as a tan solid. MP: 293-5° C.; 1H-NMR (DMSO-d6) δ 11.63 (s, 1H), 9.45 (d, 2H), 8.74 (s, 2H), 8.22 (s, 1H), 7.74 (d, 1H), 7.43-7 (t, 1H), 7.37-9 (d, 1H), 7.34 (s, 1H), 7.12-3 (d, 2H), 4.12 (m, 1H), 3.50 (m, 1H), 3.25 (s, 1H), 2.80-1 (d, 9H), 2.61-4 (m, 2H); LC/MS (ESI+): 437 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([C:17](=[O:37])[NH:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:21][C:20]=2[Cl:36])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([C:17]([NH:18][C:19]2[C:20]([Cl:36])=[CH:21][C:22]([C:26]([F:35])([C:27]([F:28])([F:29])[F:30])[C:31]([F:32])([F:34])[F:33])=[CH:23][C:24]=2[Cl:25])=[O:37])=[CH:16][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
Tert-butyl (2-chloro-4-{[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-phenyl]carbamoyl}benzyl)carbamate (0.85 g) was dissolved in methylene chloride (15 ml). Trifluoroacetic acid (2 ml) was added to the solution, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (15 ml), and an aqueous solution of potassium carbonate was added to the solution under stirring. The organic phase was separated and the aqueous layer was extracted with methylene chloride and dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (0.65 g) of 4-(aminomethyl)-3-chloro-N-[2,6-dichloro-4-(1,1,1,2,3,3,3heptafluoro propan-2-yl)-phenyl]benzamide. The crude product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([O:26][NH2:27])[CH2:23][CH2:24]C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:27]([O:26][CH2:22][CH2:23][CH3:24])[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCON
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Product: CCCOn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 187 and using 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid and O-n-butylhydroxylamine. A colorless powder (280 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[I:14])=[O:4].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[N:9]=[C:8]2[I:14])=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc2[nH]nc(I)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
In 50 mL R. B. flask, to a solution of 3-iodo-1H-indazole-5-carboxylic acid methyl ester (0.2 g, 0.66 mmol) in DCM (10 mL) was added 3,4-dihydropyran (0.117 g, 1.32 mmol) at 5° C. followed by the addition of PTSA (0.038 g, 0.264 mmol). The reaction was stirred for 2 h at RT, quenched with water (25 mL) and extracted with DCM (50 mL). The organic layer was separated and washed with water (2×25 mL) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with n-pentane to give 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole-5-carboxylic acid methyl ester (0.15 g, 58%) as off white solid. MS (ESI, pos. ion) m/z: 302.7 (M-THP+1); 1H-NMR (300 MHz DMSO-d6): δ ppm 8.24 (t, 1 H, J=9 Hz), 8.13 (dd, 1 H, J=8.7, 1.5 Hz), 7.60 (d, 1 H, J=9 Hz), 5.73 (dd, 1 H, J=9.6, 2.7 Hz), 4.95 (m, 1H), 3.96-4.04 (m, 4H), 3.75-3.78 (m, 1H), 3.52-3.53 (m, 1H), 2.52-2.56 (m, 1H), 2.05-2.17 (m, 2H), 1.58-1.84 (m, 4H).
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:22]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].C(=O)(OCC)O[CH2:39][CH3:40]>CO>[F:36][C:33]([F:34])([F:35])[S:30]([N-:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:24])=[O:25])(=[O:31])=[O:32].[CH2:39]([P+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:40]
Reactant: CCOC(=O)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 320.3 g (1.14 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 264.3 g (2.2 mol) of diethyl carbonate was also added after 1 hour of reaction. The reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 2 hours of reaction at temperature of 180° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 599.5 g of ethyl triphenyl phosphonium bis(trifluoromethyl sulfonyl) amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[N:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[C:14]=[O:15].C(N(CC)CC)C>C1COCC1>[NH:20]1[C:21]2[C:17](=[C:16]([NH:13][C:14](=[O:15])[O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2[nH]ccc12)OCc1ccc(C(F)(F)F)cc1
Yield: 53.8 %

Procedure:
[4-(Trifluoromethyl)phenyl]methanol (0.09 g, 0.55 mmol) and the product of Example 80A (0.08 g, 0.5 mmol) in THF (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 50% hexane:ethylacetate to provide the title compound as an oil (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 5.32 (s, 2H), 6.73 (s, 1H), 7.0 (t, 1H), 7.11 (d, 1H), 7.23 (t, 1H), 7.38 (d, 1H), 7.66 (d, 2H), 7.78 (d, 2H), 9.52 (s, 1H), 11.08 (s, 1H). Anal. Calcd. for C17H13N2F3O2: C, 61.08; H, 3.92; N, 8.38. Found: C, 60.97; H, 4.21; N, 8.17.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[O:21]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:26][CH:23]3[CH2:24][CH2:25][O:21][CH2:22]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=CC1CCOC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCC3CCOC3)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and tetrahydro-furan-3-carbaldehyde using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=363.4 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([F:32])[CH:34]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Reactant: Nc1cccc(F)c1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)cccc23)c1
Yield: 60 %

Procedure:
N-(tert-Butyl)-5-(4-chloro-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (1.00 g, 2.21 mmol) in 3-fluoroaniline (2.94 g, 26.5 mmol) was heated in a sealed tube at 100° C. for 12 h. On cooling, the volatile components were removed under reduced pressure and the resulting residue was purified by combiflash (REDISEP®, silica gel, 24 g, 60% EtOAc/hexanes) to obtain N-(tert-butyl)-5-(4-((3-fluorophenyl)amino)-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (0.70 g, 60%) as a brown solid. LCMS (Condition 11): retention time 1.20 min, [M+1]=528.4. 1H NMR (400 MHz, DMSO-d6) δ 1.94 (s, 9 H), 6.50 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 6.76 (td, J=2.5 Hz, J=8.4 Hz, 1 H), 7.19-7.25 (m, 2 H), 7.53-7.66 (m, 6 H), 7.88-7.93 (m, 3 H), 8.05 (dd, J=6.8 Hz, J=8.4 Hz, 1 H), 8.54 (t, J=2.0 Hz, 1 H), 9.15 (d, J=2.0 Hz, 1 H), 9.16 (d, J=2.0 Hz, 1 H).