Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[OH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH2:32])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]>C(O)C>[OH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH:32][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(CN1CCC[C@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@H]1CO)c1ccccc1S2
Reaction time: 16 h

Procedure:
3-Methylbutylamine (1.74 cc) is added to a solution of 10-{1-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (1.20 g) in absolute ethanol (20 cc). The mixture is brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is diluted with ethyl acetate (100 cc), washed with distilled water (2×50 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) before being purified by chromatography on a column (height: 14.5 cm; diameter: 2.8 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa) eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 65:35 (1.2 liters) and 35:65 (1.2 liters), collecting 60-cc fractions. Fractions 5 to 13 are combined and evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-{1-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (0.64 g) in the form of a yellow resin.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.S(Cl)(Cl)=O.[CH3:17][C:18]1[C:26]2[C:25]([NH2:27])=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:19]=1>>[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:27][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:19]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5ccccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Imidazo[1,2-a]pyridine-3-carboxylic acid (62 mg, 0.38 mmol) was dissolved neat in thionyl chloride (112 mL, 1.5 mmol). The reaction mixture was stirred at ambient temperature for 1 hour before concentrating and drying under high vacuum for 16 hours. The resulting solid was dissolved in tetrahydrofuran (2 mL). 3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (97 mg, 0.38 mmol) was added and the reaction was stirred at 70° C. in a sand bath for 6 hours. The mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The ethyl acetate layer was washed with water and brine before drying over sodium sulfate and concentrating. Preparative Thin Layer Chromatography (Silica, 1 mm) of the crude material, eluting with 10% MeOH/DCM, gave N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (48 mg) in a band with Rf=0.6. MS m/z 397.3 (M+1, APCI+).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.Cl.Cl.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH2:34][NH2:35])=[C:28]2[CH2:27][CH2:26]1>>[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH2:34][NH:35][C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([NH:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([CH3:22])([CH3:1])[CH2:3][CH2:4][NH:5]4)=[CH:10][CH:9]=3)=[O:21])=[C:28]2[CH2:27][CH2:26]1
Reactant: NCc1ccnc2c1CCN2
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Agent: Cl
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 429 (M+H). Calc'd. for C25H28N6O—428.54.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
To a mixture of 2-chloro-N-(4-fluorophenyl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (230 mg, 0.423 mmol), pyridine-4-boronic acid (57 mg, 0.463 mmol) and Pd(Ph3P)2Cl2 (30 mg, 0.042 mmol) in dioxane (4 mL), aq. Na2CO3 (135 mg, 1.27 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 2 h. It was concentrated in vacuo. The residue was triturated. The solid was collected by filtration (86 mg). The filtrate was purified by HPLC to give 2-chloro-N-(4-fluorophenyl)-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:34][CH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: NCC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: NCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 44.8 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(aminomethyl)azetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 42 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25](O)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][N:39]([C:25]([C:21]2[N:22]([CH3:24])[CH:23]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:20]=2)=[O:26])[CH2:38]1
Reactant: CN(C)C1CCNC1
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3cc(C(=O)N4CCC(N(C)C)C4)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 9 starting from 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (Example 87A, Step 8) and N,N-dimethylpyrrolidin-3-amine. LCMS (M+H)+: m/z=558.3.
Reaction SMILES: [N:1]([CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([OH:7])=O)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[N:1]([CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([NH:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: [N-]=[N+]=NC(Cc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Azido-3-phenylpropanoic acid (J. T. Lundquist IV, J. C. Pelletier, Org. Lett. 2001, 3, 781-783) (112 mg, 0.588 mmol) and HOBt (108 mg, 0.705 mmol) were suspended in CH2Cl2 (2 mL), and the mixture was cooled to 0° C. under Ar(g). DIC (107 μL, 0.705 mmol) was added, and the resulting mixture was stirred for 30 min. Benzyl amine (122 μL, 1.06 mmol) was then added, and the mixture was allowed to warm to room temperature and then stirred overnight under Ar(g). The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 15% EtOAc/hexanes, to give the required amide 2b as a white solid (117 mg, 0.418 mmol, 71% yield).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH2:23][C@@H:24]3[CH2:27][CH2:26][N:25]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]=2)(=O)=O)=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-:53]>C1COCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][C@H:24]1[CH2:23][O:22][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([C@@H:14]2[CH2:15][C@H:13]2[CH2:12][CH2:11][F:53])[CH:21]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@H]2c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCF)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
A mixture of the p-toluenesulfonate (237 mg, 0.47 mmol) and 5 mL of 1.0 M solution of n-Bu4NF in THF was stirred at room temperature for 10 h. The reaction mixture was concentrated in vacuo. The residue was purified by CC (SiO2, 50-60% EtOAc in hexane eluent) to give 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1R,2S)-2-(2-fluoroethyl)cyclopropyl]pyridine as a viscous oil (160 mg, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 8.06 (s, 1H), 6.84 (s, 1H), 4.78-4.51 (m, 3H), 4.37-4.22 (m, 1H), 4.11 (dd, J=10.1, 2.7 Hz), 3.87 (t, 2H, J=7.6 Hz), 2.36-2.21 (m, 2H), 1.75-1.66 (m, 3H), 1.42 (s, 9H), 1.12-0.96 (m, 1H), 0.95-0.82 (m, 2H). MS (ESI) m/z 351 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[O:23][C:24](=[O:38])[C:25]2[C:30]([C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.[Br:39]C(Br)(Br)Br.C(Cl)Cl>CO>[Br:39][CH2:21][C:22]1[O:23][C:24](=[O:38])[C:25]2[C:30]([C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: BrC(Br)(Br)Br
Reactant: O=c1oc(CO)c(-c2ccccc2)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.6 %

Procedure:
Triphenylphosphine (250 mg, 0.953 mmol) was added to a solution of 3-(hydroxymethyl)-4-phenyl-1H-isochromen-1-one (intermediate B2, 185 mg, 0.733 mmol) and perbromomethane (316 mg, 0.953 mmol) in DCM (3.7 ml, 57.5 mmol), and the resulting mixture was stirred at RT for 3 days, adding the reagents several times to achieve completion (overall 4 equivalents). The reaction was taken up with MeOH then concentrated under reduced pressure. The crude was purified over a Biotage Silica 50 g SNAP cartridge with a gradient of hexane and EtOAc to give the title compound (0.11 g, 47.6%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (1 g, 3.98 mmol), 4,4,5,5-tetramethyl-2-[4-(methylsulfonyl)phenyl]-1,3,2-dioxaborolane (1.236 g, 4.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.230 g, 0.199 mmol) were taken up in THF (14 mL)/2 N Na2CO3 (6 mL) The reaction was stirred at 80° C. overnight. Room temperature was attained and the resulting precipitate was collected by filtration, washed with water and triturated in EtOH to give the title compound as a yellow solid.
Reaction SMILES: CC#N.C([O:6][P:7]([C:12]([CH3:16])([CH3:15])[CH2:13][NH2:14])(=[O:11])[O:8]CC)C.C[Si](Br)(C)C>CO>[NH2:14][CH2:13][C:12]([P:7](=[O:6])([OH:11])[OH:8])([CH3:16])[CH3:15]
Reactant: CCOP(=O)(OCC)C(C)(C)CN
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: CC#N
Product: CC(C)(CN)P(=O)(O)O

Procedure:
A solution of CH3CN (30 mL) of crude 6 (2.5 g) was cooled to 0° C., and treated with TMSBr (8 g, 52 mmol) for 5 hr. The reaction mixture was stirred with methanol for 1.5 hr at room temperature, concentrated, recharged with methanol, concentrated to dryness to give crude 7 which was used for next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=2)[C:3]=1[N+:32]([O-])=O.[H][H]>CO.[Pd]>[NH2:32][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3[N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Yield: 84.1 %

Procedure:
To a solution of 4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)-3-nitropyridine (step 3, 11.4 g, 23.6 mmol) in methanol (250 mL) was added 10% Pd—C (2.0 g). The resulting mixture was stirred under the medium pressure of hydrogen (4.0 kgf/cm2) for 4 h. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to afford 9.0 g (85%) of the title compound as off white solids.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15](OCC)=[O:16])[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[N:6]2[N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=[C:2]2[NH:1][CH:20]=1)=[O:24])[CH3:11]
Reactant: Nc1cc(C(=O)O)n[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C(=O)O)nn2c1=O
Temperature: 120 °C
Yield: 29.9 %

Procedure:
To a solution of 5-amino-1H-pyrazole-3-carboxylic acid (600 mg, 4.7 mmol, 1 eq) in acetic acid (30 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (1.1 g, 5.2 mmol, 1.1 eq). The mixture was heated at 120° C. for 4 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol to afford the expected compound as grey powder (353 mg, 30% yield).
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1.[F:15][CH:16]([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=1[CH3:25]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[F:15][CH:16]([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:13]#[C:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([F:14])[F:1])[CH:7]=2)=[CH:20][C:19]=1[CH3:25]
Reactant: C#Cc1cccc(OCCC(F)F)c1
Reactant: Cc1cc(I)ccc1OC(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2cccc(OCCC(F)F)c2)ccc1OC(F)F

Procedure:
This compound was made in a similar manner to Example 89 Step 4 using 1-(3,3-difluoropropoxy)-3-ethynylbenzene (650 mg, 3.13 mmol) from the previous step, 1-(difluoromethoxy)-4-iodo-2-methylbenzene (818 mg, 2.88 mmol), TEA (1.45 g, 2.0 mL, 14.5 mmol), PdCl2(PPh3)2 (101 mg, 0.144 mmol), and CuI (16.4 mg, 0.0864 mmol), and DMF (4.4 mL) to provide the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2ccc(C#N)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 459 mg of 4-[4-(4-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in Step 4 in DMF (1.5 mL), 173 mg of potassium carbonate and 130 μL of methyliodide are added. The mixture is stirred 3 hours at rt, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: [N:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:11]([NH2:12])[C:7]2([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[CH2:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCSCC2)CCC1
Product: NC(c1ccccc1)C1(N2CCSCC2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=263.1 [(M+B)+], was prepared in accordance with the general method of intermediate B from 1-thiomorpholin-4-yl-cyclobutanecarbonitrile (intermediate X) and phenyllithium.
Reaction SMILES: C(O)C.[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:19](=O)[CH2:20][CH:21]([C:27](=O)[CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:6][CH2:5]1.C([O-])(=O)C.[NH4+:45]>O>[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:19]3[NH:45][C:27]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:6][CH2:5]1
Reactant: [NH4+]
Reactant: CCOC(=O)C(CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1)C(=O)COCc1ccc(OC)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OC(F)F)c(OCC3CC3)c2)[nH]c1COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To 100 ml of ethanol solution containing 14.0 g (26.8 mmol) of ethyl 2-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-oxoethyl]-4-(4-methoxybenzyloxy)-3-oxobutyrate obtained in Reference example 45-(b) was added 10.3 g (134 mmol) of ammonium acetate, the mixture was stirred at room temperature for 1 hour, and further stirred at 80° C. for 4 hours. After completion of the reaction, to the reaction mixture were added water and a saturated aqueous solution of sodium chloride, and the mixture was extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 10.3 g of the title compound as a beige solid. (Yield: 77%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:39])=[CH:5][C:6]([Cl:38])=[C:7]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[C:17]([O:33][CH2:34][CH:35]([F:37])[F:36])[C:18]([C:20]([NH:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]4)=[O:21])=[CH:19][C:12]=3[N:11]=2)[CH:8]=1.[F:40][C:41]([F:49])([F:48])[C:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:38][C:6]1[CH:5]=[C:4]([F:39])[C:3]([CH2:2][NH:1][C:45]([C:42]2([C:41]([F:49])([F:48])[F:40])[CH2:44][CH2:43]2)=[O:46])=[CH:8][C:7]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([O:33][CH2:34][CH:35]([F:36])[F:37])[C:18]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([F:31])([F:32])[F:30])[CH2:25][CH2:24]3)=[O:21])=[CH:19][C:12]=2[N:11]=1
Reactant: Cn1c(Nc2cc(CN)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (c) using 2-[5-(aminomethyl)-2-chloro-4-fluoro-phenyl]amino-6-(2,2-difluoroethoxy)-1-methyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide (150 mg; 0.26 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (40 mg; 0.26 mmol), HBTU (99 mg; 0.26 mmol), TEA (53 mg; 0.52 mmol) and DMF (4 mL). Yield: 39 mg (21%). 400 MHz 1H-NMR (DMSO-d6, ppm) 8.40 (1H, t, J=5.8 Hz) 8.32 (1H, s) 7.90-7.82 (2H, m) 7.78-7.74 (1H, m) 7.44 (1H, d, J=9.6 Hz) 7.23-7.19 (1H, m) 6.63-6.34 (1H, m) 4.51-4.40 (2H, m) 4.29 (2H, d, J=5.8 Hz) 3.78-3.65 (4H, m) 2.28-2.17 (1H, m) 2.03-1.97 (2H, m) 1.91-1.85 (2H, m) 1.39-1.19 (8H, m). MS m/z: 714, 716 [M+H]+.