Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N[C:11]1C=CC=C(C)C=1.C(N[C:22]1[C:35]2[C:34](=[O:36])[C:33]3[C:28](=[C:29]([N+:37]([O-:39])=[O:38])[CH:30]=[CH:31][CH:32]=3)[C:27](=[O:40])[C:26]=2[C:25]([NH:41][C:42]2[CH:49]=CC(OC)=C[CH:43]=2)=[CH:24][CH:23]=1)(C)C>>[CH:42]([NH:41][C:25]1[C:26]2[C:27](=[O:40])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][C:29]=3[N+:37]([O-:39])=[O:38])[C:34](=[O:36])[C:35]=2[C:22]([NH:9][C:6]2[CH:7]=[C:8]([CH3:11])[CH:3]=[CH:4][CH:5]=2)=[CH:23][CH:24]=1)([CH3:49])[CH3:43]
Reactant: COc1ccc(Nc2ccc(NC(C)C)c3c2C(=O)c2c(cccc2[N+](=O)[O-])C3=O)cc1
Reactant: Cc1cccc(N)c1
Reactant: COc1ccc(N)cc1
Product: Cc1cccc(Nc2ccc(NC(C)C)c3c2C(=O)c2cccc([N+](=O)[O-])c2C3=O)c1

Procedure:
If the procedure indicated above is followed but the 8-nitro compound is replaced by a mixtue of 1-isopropylamino-4-bromo-5- and -8-nitroanthraquinone and 180 g of p-anisidine are used instead of m-toluidine as the base, 48 g of a mixture consisting of 1-isopropylamino-4-p-anisidino-5-nitroanthraquinone and 1-isopropylamino-4-p-anisidine-8 -nitroanthraquinone are obtained after dilution with 300 ml of methanol and filtration at 10°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][N:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1.[N+](=[CH2:33])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH:15]2[CH2:33][CH2:16]2)=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:20][N:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1
Reactant: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1Oc1ccc(S(=O)(=O)CC)cn1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2c(C3CC3)c(CC(=O)OC)cc3ccc(F)cc23)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled solution of [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-3-vinyl-naphthalen-2-yl]-acetic acid methyl ester (6.0 mg, 0.014 mmol, methyl ester of example 17-1) in tetrahydrofuran, was added a solution of diazomethane (0.1 M, 5 mL) in diethyl ether at 0° C. under an argon atmosphere, followed by palladium acetate (1 mg) in two portions. After being stirred at 0° C. for 2 hours, the reaction mixture was treated with acetic acid (0.2 mL) to quench the reaction, and then filtered. The filtrate was concentrated in vacuo to afford the crude product of [3-cyclopropyl-4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1C=CN=C1)=[O:2].[F:13][C:14]([F:33])([F:32])[C:15]1[CH:16]=[C:17]([S:21]([N:24]2[CH2:29][CH2:28][CH:27]([O:30]N)[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.[CH2:34](N(CC)CC)C.C(N)CC>C(Cl)Cl>[CH2:12]([NH:8][C:1]([NH:3][O:30][CH:27]1[CH2:28][CH2:29][N:24]([S:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:33])([F:32])[F:13])[CH:16]=2)(=[O:23])=[O:22])[CH2:25][CH2:26]1)=[O:2])[CH2:11][CH3:34]
Reactant: CCN(CC)CC
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCCN
Solvent: ClCCl
Product: CCCNC(=O)NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
1,1′-Carbonyldiimidazole (194 mg, 1.20 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol) and triethylamine (121 mg, 1.20 mmol) in CH2Cl2 (5 ml) and stirred at room temperature for 17 hours. Propan-1-amine (35.0 mg, 0.60 mmol) was added to the reaction mixture and stirred at room temperature for another 17 hours. The resulting precipitaion was collected, washed with aqueous 1 N HCl solution (10 ml×3), aqueous NaHCO3 solution (10 ml×3), diethyl ether (10 ml×2) to give 1-propyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea (215 mg, 88%) as a white solid: LCMS: 410 [M+1]+. 1H NMR (DMSO-d6) δ: 0.77 (t, 3H), 1.37 (m, 2H), 1.73 (m, 2H), 1.88 (m, 2H), 2.87 (m, 4H), 3.17 (m, 2H), 3.61 (t, 1H), 6.63 (t, 1H), 7.90 (m, 2H), 8.08 (m, 2H), 8.79 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[C:8]([CH3:14])=[N:7]1.[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[N:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[ClH:1].[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[C:8]([CH3:14])=[N:7]3)[CH2:29][CH2:30]2)[CH:22]=[C:21]([C:31]([F:32])([F:33])[F:34])[N:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1nn(CCCCCl)c(=O)[nH]c1=O
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Product: Cc1nn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)[nH]c1=O
Product: Cl

Procedure:
2-{4-[4-(2-tert-Butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-6-methyl-2H-[1,2,4]triazine-3,5-dione hydrochloride was prepared from 2-(4-chloro-butyl)-6-methyl-2H-[1,2,4]triazine-3,5-dione and 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethyl-pyrimidine by analogy to the process described in example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C@@H:33]1[O:37][C:36](=[O:38])[NH:35][CH2:34]1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:35]2[CH2:34][C@H:33]([CH3:32])[O:37][C:36]2=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: C[C@H]1CNC(=O)O1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 82.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (437 mg) was obtained.
Reaction SMILES: [Mg].BrC(Br)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)#[N:15]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.67 g (27.42 mmol) of magnesium turnings were dried by heating under argon and, after cooling to RT, 30 ml of tetrahydrofuran and 2 ml of dibromoethane were added. At 0° C., 5.00 g (26.12 mmol) of 4-chlorobromobenzene in 30 ml of tetrahydrofuran were slowly added to the mixture, and the mixture was stirred at RT for 30 min. Addition of 3.77 g (28.73 mmol) of 4-cyanobenzaldehyde in 30 ml of tetrahydrofuran was followed by stirring for 3 h. The THF was removed from the reaction solution in a rotary evaporator, and the residue was taken up in dichloromethane. It was washed with 1N hydrochloric acid, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The precipitate which separated out of the oily residue was filtered off, washed with diethyl ether and then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator, and the aqueous residue was extracted with dichloromethane. Removal of the solvent resulted in 1.43 g (23% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:48])(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:48])(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([O-:46])=[O:45]
Reactant: O=C(O)CCCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of glutaric acid (0.037 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. The solution was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered to give Nilotinib glutarate form I.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]CCCC.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.OS(O)(=O)=O>C1COCC1>[CH3:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:21]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]1=2
Reactant: CN(c1ccccc1)c1ccccc1Br
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1c2ccccc2C2(CCCCC2)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Cyclohexanone (0.43 mL, 0.412 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.3 g (30%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.53 (m, 4H), 2.10 (m, 4H), 3.12 (s, 3H), 5.65 (m, 1H), 6.66 (m, 3H), 7.18 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 22.0, 23.0, 25.6, 28.2, 39.2, 113.7, 116.9, 125.6, 126.3, 127.7, 128.2, 128.5, 130.3, 137.9, 142.8, 145.6, 149.0. HRMS (ESI) calc for C19H21N [M+H]+ 264.1747, found 264.1758. IR (KBr plate) 693 (m), 747(m), 1069 (s), 1155 (m), 1263 (m), 1345 (m), 1499 (s), 1602(s), 2853 (m), 2921 (s) cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:15])[CH2:11]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O-:19])([O-])=[O:17].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:19][C:16](=[O:17])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:10]([OH:15])[CH3:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 74.4 %

Procedure:
To a stirred solution of 4-tert-butoxycarbonylamino-3-hydroxy-butyric acid (2.0 g) in dry DMF (30 ml) at room temperature was added K2CO3 (2.8 g). After 15 min. benzyl bromide (1.7 g) was added. After 16 h the mixture was poured into 200 ml of water and extracted into EtOAc (200 ml×2). The combined organics were washed with 1N NaOH (40 ml); water (40 ml×2); brine (40 ml); dried over MgSO4; filtered, and concentrated under reduced pressure to give an oil. Purification by Flash 40 chromatography using a silica gel column and eluting with 30% EtOAc/hexane gave 2.1 g of the title compound as a colorless oil. 1H nmr (400 MHz, CDCl3) δ1.43 (s, 9H), 2.53 (m, 2H), 3.07-3.14 (m, 1H), 3.30-3.34 (m, 1H), 4.09-4.13 (m, 1H), 4.95 (broad s, 1H), 5.14 (s, 2H), 7.34 (m, 5H).
Reaction SMILES: C[Mg]Cl.Br[C:5]1[CH:16]=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[CH:7][C:6]=1[F:17].[CH2:18]([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.Cl>O1CCCC1>[C:9]([C:8]1[CH:15]=[CH:16][C:5]([B:27]([OH:28])[OH:26])=[C:6]([F:17])[CH:7]=1)(=[O:10])[CH3:18]
Reactant: [Li]CCCC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(B(O)O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium chloride (3 M in toluene/tetrahydrofuran) (2.54 mL, 7.6 mmol) was added to a 0° C. solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (500 mg, 1.9 mmol) in tetrahydrofuran (10 mL). After stirring at 0° C. for 30 min, the reaction mixture was cooled to −78° C. and n-butyllithium (2.6 mL, 4.2 mmol) was added. After stirring at −78° C. for 2 h, triisopropylborate (1.5 mL, 6.7 mmol) was added and the reaction allowed to warm slowly to ambient temperature over 3 h. 1 M hydrochloric acid (5 mL) was added and the reaction stirred for 10 min. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, saturated with sodium chloride and extracted with diethyl ether. Combined ethereal extracts were extracted with 0.5 N aqueous sodium hydroxide (6×5 mL). Combined extracts were acidified, saturated with sodium chloride and reextracted with ethyl acetate. The combined extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford (4-acetyl-2-fluorophenyl)boronic acid which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:13]=[C:12](O)[C:11]3[CH:15]([CH3:18])[CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1.[Na+].[I-:21]>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:13]=[C:12]([I:21])[C:11]3[CH:15]([CH3:18])[CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: [I-]
Reactant: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(O)c21
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(I)c21
Temperature: 25 °C

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (200 mg, 0.72 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid. The residual POCl3 was removed by azeotrope with chloroform. To a suspension of the crude iminochloride in a 57% HI solution in water (5 ml) at rt was added NaI (540 mg, 3.60 mmol, 5 eq). The reaction mixture was stirred at rt overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue 2-(5-chloro-2-fluorophenyl)-4-iodo-5-methyl-6,7-dihydro-5H-cyclopentapyrimidine which was not further purified.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)[C:15](Cl)=[O:16]>C(Cl)CCl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:15]=[O:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-(trifluoromethyl)benzamide (0.200 g, 1.05 mmol), EDC (10 mL) and oxalyl chloride (0.15 mL, 1.58 mmol) to afford 0.200 g of the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1.[CH3:29][C:30]1(C)C(C)(C)OB(C=C)O1.C(N(CCCC)CCCC)CCC>CN(C)C=O.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[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([CH:29]=[CH2:30])=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1Cl
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=Cc1nn(C2CCCCO2)c2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ncc12
Temperature: 95 °C
Reaction time: 15 h

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.2 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (44 μL, 0.26 mmol) (Aldrich Cat. No. 633348), tributylamine (54 μL, 0.22 mmol) and dichloro[bis(triphenylphosphoranyl)]palladium (5 mg, 0.007 mmol) in N,N-dimethylformamide (1 mL) in a reaction vial was degassed and sealed. The mixture was stirred at 95° C. for 15 h. After cooling it was equally split into two parts. The material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[C:12]([CH:21]=O)=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[C:4]([O:23][CH3:24])[CH:3]=1.[Si]([C:29]#[N:30])(C)(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(Cl)Cl.CO.[Zn+2].[I-].[I-]>[F:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:12]=2[CH:21]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:29]#[N:30])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CNC(C#N)c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1

Procedure:
To a solution of 203 mg of 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (INTERMEDIATE 31) in 2 mL of CH2Cl2 was added 100 μL of TMSCN, and then 1 mg of ZnI2. The mixture was stirred for 30 min at r.t. p-Methoxybenzylamine (157 μL) in 2 mL of MeOH was added and the mixture was heated to reflux for 1.5 h. The reaction mixture was cooled and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes followed by a linear gradient of 2→100% EtOAc in hexanes over 10 CV to provide the title compound. Mass spectrum (ESI) 487.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:8][CH:7]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:43])=[O:2])=[CH:7][CH:8]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid methyl ester (49 mg, 0.078 mmol) in THF (3 mL) was added LiOH monohydrate (14 mg, 0.326 mmol) in water (2 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenyl)-propionic acid as a white solid (35 mg, 73%). MS (ES+) m/z [(M+H)+]: 612
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.[CH3:21][C:22]([NH:25][C:26]1[O:27][C:28]([C:35]([OH:37])=[O:36])=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)([CH3:24])[CH3:23]>O>[CH3:24][C:22]([NH:25][C:26]1[O:27][C:28]([C:35]([O:37][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Br:12])=[O:36])=[C:29]([C:31]([F:32])([F:34])[F:33])[N:30]=1)([CH3:21])[CH3:23]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Reactant: BrCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2Br)o1
Temperature: 25 °C
Yield: 145.4 %

Procedure:
A reaction vessel was charged with 100 ml of dimethylformamide, 6.11 g (50 mmol) of potassium carbonate, and 18 g (72 mmol) of o-bromobenzyl bromide. With this mixture stirred at ambient temperature under a nitrogen atmosphere, there was added 10 g (40 mmol) of 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylic acid (prepared by Example 26). The reaction mixture was stirred at ambient temperature for 18 hours. Then, the mixture was added to water and extracted three times with ethyl ether. The ether extracts were washed with large amounts of water, then dried over magnesium sulfate, and concentrated under reduced pressure to yield 24.5 g of a gold oil. This oil was subjected to Kugelrohr distillation (65°-70° C. @ 0.4 mm Hg) to yield 9.7 g of a gold oil. The remaining still residue upon standing at ambient temperature for 30 minutes formed a solid material. Trituration of this solid material in hexane at ambient temperature resulted in 11.48 g of a white solid product (m.p.=74°-77° C.) identified in Table I.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.Cl>ClCCl.O>[CH3:1][NH:2][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNCCc1ccc([N+](=O)[O-])cc1
Reaction time: 15 h

Procedure:
2.7 g (86 mmol) of methylamine are dissolved in 120 ml of dichloromethane while cooling with ice. 4.9 g (21 mmol) of 4-(2-bromoethyl)-nitrobenzene are added and the mixture is allowed to come up slowly to ambient temperature. After 15 hours stirring the solvent is eliminated in vacuo and the residue taken up in water. An acid pH is created using 2 N hydrochloric acid and the mixture is washed with dichloromethane. The aqueous phase is then adjusted to a basic pH using 4 N sodium hydroxide solution and the product is extracted with dichloromethane.