Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:34]#[N:35])[C:16]([C:19]2[CH:24]=[C:23](B3OCC(C)(C)CO3)[CH:22]=[CH:21][C:20]=2[F:33])=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([C:34]#[N:35])[C:16]([C:19]2[CH:24]=[C:23]([C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]4=[N:4][CH:3]=3)[CH:22]=[CH:21][C:20]=2[F:33])=[CH:17][CH:18]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: Fc1cccn2c(Br)cnc12
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)cccn23)ccc1F
Yield: 54.8 %

Procedure:
3-Bromo-8-fluoroimidazo[1,2-α]pyridine (0.10 g, 0.47 mmol) and 4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (0.28 g, 0.83 mmol) were coupled following the procedure in Example 1 to afford 4,2′-difluoro-5′-(8-fluoroimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile as a white amorphous solid (90 mg, 55%): δH (360 MHz, CDCl3) 6.79-6.83 (1H, m), 6.94 (1H, dd, J 8 and 8), 7.73-7.46 (2H, m), 7.53-7.65 (4H, m), 7.73 (1H, s), 8.25 (1H, d, J 7); m/z (ES+) 350 (M++H).
Reaction SMILES: C1(CNC(C2NC=C(C(C3[C:16]([C:21]4[CH:26]=[CH:25][C:24](F)=CC=4)=[N:17]OC=3C)=O)C=2)=O)CC1.[F:28][C:29]1[CH:30]=[C:31]([C:36]2[C:40]([C:41]([C:43]3[CH:44]=[C:45]([C:48](=[O:53])C(Cl)(Cl)Cl)[NH:46][CH:47]=3)=[O:42])=[C:39]([CH3:54])[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35].C1(N)CCCC1>>[CH:16]1([NH:17][C:48]([C:45]2[NH:46][CH:47]=[C:43]([C:41]([C:40]3[C:36]([C:31]4[CH:32]=[CH:33][C:34]([F:35])=[C:29]([F:28])[CH:30]=4)=[N:37][O:38][C:39]=3[CH3:54])=[O:42])[CH:44]=2)=[O:53])[CH2:21][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Agent: NC1CCCC1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCCC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and cyclopentylamine (commercially available) in 38.1 yield. (m/e): 400.1 (MH+; 100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:11]1([CH2:2][C:3]2[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: N#Cc1ncccc1CBr
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncccc1Cn1ccnc1

Procedure:
Synthesized from 4a (600 mg, 3.04 mmol), imidazole (829 mg, 12.1 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. Yield: 476 mg, 2.58 mmol, 85%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.41 (s, 2H), 6.97 (t, J=1.3 Hz, 1H), 7.15 (t, J=1.3 Hz, 1H), 7.36-7.38 (m, 1H), 7.51 (dd, J=8.2, 4.7 Hz, 1H), 7.63 (s, 1H), 8.68 (dd, J=4.7, 1.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=47.1, 115.3, 119.1, 127.4, 130.9, 132.5, 135.6, 137.0, 137.5, 150.7; MS (ESI): m/z=185.08 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1CC=C.C[N+]1([O-])CC[O:19]CC1.[CH3:23][C:24]([CH3:26])=[O:25]>O.O=[Os](=O)(=O)=O>[OH:25][CH:24]([CH2:26][OH:19])[CH2:23][C:3]1[C:2]([CH3:1])=[C:10]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:11])[O:8][CH2:9]2
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1ccc2c(c1C)COC2=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1c(CC(O)CO)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one (see step A for 1-3), (2.00 g, 10.6 mmol) in acetone (30 mL) and water (10 mL) was added OsO4 (0.27 g, 1.06 mmol) and NMO (6.70 g, 11.7 mmol), the solution was stirred at 25° C. for 18 h. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with CH2Cl2 (3×40 mL). The organic layers were combined, washed with brine (2×40 mL), dried with MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (0-10% methanol in dichloromethane) to give the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].FC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1>>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cc(N)ccc1F
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 4-fluoro-3-methoxyaniline using a method similar to that described for D1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH2:9]>CS(C)=O.C(OCC)C>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:9])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: Oc1ccc(SSc2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 96 %

Procedure:
25.0 g of para-hydroxy thiophenol (Wako Pure Chemical Industries, Ltd.) was dissolved in 100 ml of dimethyl sulfoxide (Kanto Chemical Co., Ltd.) at 0 degree C. The reaction solution was stirred for 24 hours at 65 degree C. and cooled to 0 degree C. after the completion of the reaction. Then the mixture was diluted with 100 ml of diethyl ether (Wako Pure Chemical Industries, Ltd.). Water was added to this solution and the aqueous phase was extracted with 50 ml of diethyl ether three times. Then the organic phase was dried by using sodium sulfate (Wako Pure Chemical Industries, Ltd.) and recrystallized in chloroform (Wako Pure Chemical Industries, Ltd.). 4,4′-disulfanediyldiphenol was obtained (23.8 g, yield 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[CH:4]([NH:17][C:18](=[O:20])[CH3:19])[CH2:3]1.[CH3:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=1)=[O:25]>>[CH3:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34]([NH:13][C:11]2[CH:10]=[CH:9][C:8]3[C:2]([CH3:21])([CH3:1])[CH2:3][CH:4]([NH:17][C:18](=[O:20])[CH3:19])[C:5](=[O:16])[NH:6][C:7]=3[CH:12]=2)[N:33]=1)=[O:25]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(C)=O)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1221d. Title compound was isolated as a brown solid. (51 mg, 36%) MP=205-210, LCMS 530 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 11.70 (s, 1H), 9.80 (s, 1H), 9.63 (s, 1H), 8.47 (d, J=4.8 Hz, 1H), 8.26-8.24 (m, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.47 (s, 1H), 7.35-7.30 (m, 2H), 4.32-4.29 (m, 1H), 2.78 (d, J=4.1 Hz, 3H), 2.14-2.10 (m, 1H), 1.94-1.90 (m, 1H), 1.87 (s, 3H), 1.38 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][CH:13]=[CH:14][C:7]=12)([O-:5])=[O:4].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:14]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[N+:3]([O-:5])=[O:4])[NH:12][CH:13]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccnc2[nH]ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccnc2[nH]cc(Br)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 316 μl (6.13 mmol) of bromine are added dropwise to a solution of 1.00 g (6.13 mmol) of 4-nitro-1H-pyrrolo[2,3-b]pyridine (Antonini, Ippolito; Claudi, Francesco; Cristalli, Gloria; Franchetti, Palmarisa; Grifantini, Mario; Martelli, Sante; J. Med. Chem. 1982, 25, 1258-1261.) in 50 ml of dichloromethane. After 1 h of stirring at 0° C. and 1 h of stirring at room temperature, the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution. The mixture is then extracted twice with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed under reduced pressure. The residue is taken up in a mixture of cyclohexane/ethyl acetate and the precipitate formed is filtered off.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C(O)c1ccncc1F
Product: Cc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 4-methylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.13 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.25 (d, 2H, J=7.9 Hz), 7.15 (d, 2H, J=7.8 Hz), 4.50 (s, 2H), 2.28 (s, 3H). [M+H] calc'd for C14H14N2O2, 243. found 243.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[Cl:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([CH2:20][CH2:21][CH:22]=O)=[CH:15][C:14]=1[F:24]>>[Cl:12][C:13]1[C:14]([F:24])=[CH:15][C:16]([CH2:20][CH2:21][CH:22]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)=[CH:17][C:18]=1[F:19]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1cc(F)c(Cl)c(F)c1
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(Cl)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (4.012 mmol) and 3-(4-chloro-3,5-difluoro-phenyl)-propionaldehyde (1.030 g; 5.034 mmol) afforded 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.78 min.; [M+H]+=451.76 g/mol.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>CCO.O>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=NO)s1
Yield: 75.7 %

Procedure:
To a solution of 5-methylthiophene-2-carboxaldehyde (4.0 g, 31.8 mmol; Aldrich) in EtOH (24 mL) was added a solution of hydroxylamine hydrochloride (3.28 g, 47.2 mmol; Aldrich) in water (6 mL) and then a solution of sodium acetate (5.20 g, 67.5 mmol) in water (6 mL after which the mixture heated at reflux for 1 h. The mixture, after cooling, was concentrated in vacuo, and the residue diluted with water and extracted with CH2Cl2 (25 mL×2). The combined extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated. The residual oily solid was triturated with Et2O (˜20 mL) to obtain 3.4 g (76% yield) of the title compound as an off-white powder: HPLC: 1.69 min (at 254 nm); LC/MS m/z 142 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 2.53 (3H, s, CH3), 6.77 (1H, d, J=3.7 Hz, Th—H), 7.21 (1H, d, J=3.7 Hz, Th—H), 7.63 (1H, s, Th—H), 9.22 (1H, br, OH); 1H NMR (500 MHz, DMSO-d6) δ ppm 2.46 (3H, s, CH3), 6.83 (1H, dd, J=3.5, 1 Hz, Th—H), 7.26 (1H, d, J=3.5 Hz, Th—H), 7.71 (1H, s, Th—H), 11.65 (1H, s, 6-NOH); 13C NMR (125.8 MHz, CDCl3) δ ppm 15.4 (CH3), 125.0 (CH), 129.1 (C), 132.5 (CH), 141.4 (CH), 147.0 (C); HRMS (ESI) calcd for C6H8NOS (M+H) 142.0327, found 142.0327 (δ+0.3 ppm). 1H— and 13C-NMR indicated this material was predominantly one geometric isomer. The mother liquor, after concentration gave 0.79 g (18% yield) of the title compound, whose 1H-NMR indicated a ˜1:1 mixture of two geometric oxime isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
A mixture of 3,4-difluorobenzaldehyde (2.00 g, 14.8 mmol), 6-chloropyridin-3-ol (1.82 g, 14.1 mmol) and potassium carbonate (2.14 g, 15.5 mmol) in N,N-dimethylformamide (DMF) (25 mL) was stirred at 110° C. for 12 h, diluted with ethyl acetate (50 mL), washed with water (50 mL×2). The organic part was separated, dried over anhydrous Na2SO4, filtered and concentrated. Purification via silica gel (3% ethyl acetate in petroleum ether) afforded the title product (2.8 g)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-piperidin-4-yl-morpholine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as an off white solid (50% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography to give 336 as an off white solid (21% yield). NMR (CDCl3, 400 MHz), 1.60-1.67 (2H, m), 1.86 (2H, d, J=12.2), 2.14 (211, t, J=10.6), 2.17-2.23 (1H, m), 2.57-2.59 (4H, m), 3.05 (2H, d, J=11.7), 3.73-3.75 (4H, m), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=497
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:35]([CH3:36])=[C:34]([CH2:37][CH3:38])[N:33]=[C:32]([CH2:39][N:40]([CH3:42])[CH3:41])[N:31]=1>>[CH2:37]([C:34]1[C:35]([CH3:36])=[C:30]([N:16]2[CH2:15][C:14]3[CH:20]=[C:10]([C:8]4[CH:9]=[C:4]5[N:3]=[C:2]([CH3:1])[NH:21][C:5]5=[N:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[O:19][CH2:18][CH2:17]2)[N:31]=[C:32]([CH2:39][N:40]([CH3:42])[CH3:41])[N:33]=1)[CH3:38]
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CCc1nc(CN(C)C)nc(Cl)c1C
Product: CCc1nc(CN(C)C)nc(N2CCOc3ccc(-c4cnc5[nH]c(C)nc5c4)cc3C2)c1C

Procedure:
Prepared according to the method of example 6 by using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and 1-(4-chloro-6-ethyl-5-methylpyrimidin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (br s, 1H), 8.03 (br s, 1H), 7.70 (d, 1H), 7.52 (dd, 1H), 7.03 (d, 1H), 4.61 (s, 2H), 4.33-4.28 (m, 2H), 3.84-3.79 (m, 2H), 3.36 (s, 2H), 2.63 (q, 2H), 2.53 (d, 3H), 2.20 (s, 3H), 2.13 (s, 6H), 1.89 (s, 3H), 1.14 (t, 3H); MS (EI) for C26H31N7O: 458 (MH+).
Reaction SMILES: [NH4+].[N:2]#[C:3][S-:4].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][CH2:10][C:11](Cl)=[O:12])[CH3:6].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>CC#N>[CH2:5]([O:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([NH:2][C:3]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([F:23])=[C:16]([F:15])[CH:17]=1)=[S:4])=[O:12])[CH3:6]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: N#C[S-]
Reactant: Nc1ccc(F)c(F)c1
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)CCC(=O)NC(=S)Nc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of thiocyanic acid, ammonium salt (5 g, 0.065 mol) in CH3CN (42 ml) was stirred for 15 min. at r.t. 4-Chloro-4-oxo-butanoic acid ethyl ester (0.061 mol) was added dropwise and the mixture was stirred for 30 min. at 60° C. The mixture was cooled to 0° C. and then 3,4-difluoroaniline (6 mL, 0.061 mol) was added dropwise. The reaction mixture was stirred for 30 min. at r.t. The mixture was then quenched with ice-water and stirred for 15 min. at 0° C. The mixture was filtered through a sinter funnel, dried and azeotroped with toluene to remove remaining water. Yield: 16.40 g of intermediate D5 (85%, yellow solid).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH2:21])=[O:20])=[CH:14][C:13]=1[C:22]([F:25])([F:24])[F:23].[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27][C:28]([CH3:30])=O.P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1COCC1>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:27]([C:26]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:30])[N:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[C:13]([C:22]([F:23])([F:24])[F:25])[CH:14]=3)[C:19](=[O:20])[NH:21]2)=[CH:4][CH:5]=1)#[N:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1

Procedure:
The reaction was carried out under argon. In succession, 4-formylbenzonitrile (656 mg, 5.0 mmol), 1-[4-fluoro-3-(trifluoromethyl)phenyl]urea (1.11 g, 5.0 mmol) and ethyl acetoacetate (651 mg, 5.0 mmol) were added to a solution of ethyl polyphosphate (2.0 g; prepared from triethyl phosphate and diphosphorus pentoxide analogously to the process in Example 18A) in THF (25 ml). The mixture was stirred under reflux for 19 h and then concentrated. Ethyl acetate (150 ml) was added to the residue, and the mixture was washed successively with water (50 ml), saturated sodium bicarbonate solution (50 ml) and saturated sodium chloride solution (50 ml). The organic phase was dried over sodium sulphate and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane→cyclohexane/ethyl acetate 2:3). This gave 1.40 g (63% of theory) of the target product.
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[O:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:6]([O:5][P:4]([C:3]([C:1]#[N:2])=[CH:27][CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CCOCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (50.0 g, 282 mmol), ammonium acetate (9.0 g, 117 mmol), acetic acid (9 ml) in toluene (200 mL), tetrahydropyran-4-carbaldehyde (32.2 g, 282 mmol) were added. The reaction mixture was stirred at room temperature for two hours and then heated at reflux for 1.5 hours. After cooling down, the reaction mixture washed with saturated sodium bicarbonate solution three times, brine one time and then dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(tetrahydropyran-4-yl)-vinyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C#N.[CH3:12][N:13](CC1C=CC=CC=1)C.[C-]#N.[Na+]>C(Cl)Cl.O>[C:1]([C:12]#[N:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CC(=O)c1ccccc1
Reaction time: 2 h
Yield: 91 %

Procedure:
140.5 grams (1.0 mole) of benzoyl chloride were dissolved in 600 ml of methylene chloride. This solution was treated simultaneously with 27 grams (1.0 mole) of hydrogen cyanide and 1.83 grams (0.014 mole) of N,N-dimethyl benzyl amine. Then within 20 minutes there were fed in 171 grams of a 29.8 percent aqueous sodium cyanide solution (1.04 moles of sodium cyanide). The temperature of the reaction mixture meanwhile and for a further 2 hours was held at 15 to 35° C. Then there were added 60 grams of water and the phases separated. After removal of the hydrogen cyanide and the methylene chloride there were obtained by distillation 136 grams of crude, 91 percent benzoyl cyanide. In fractional distillation there were obtained 122 grams of pure benzoyl cyanide. This corresponds to a yield of 93% base on the benzoyl chloride employed.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH2:17]([Mg]Br)[CH3:18].Cl>O1CCCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)benzaldehyde (300 mg, 1.24 mmol) in anhydrous tetrahydrofuran (3 mL) stirred on an ice bath was added ethylmagnesium bromide (1.00 M solution in anhydrous tetrahydrofuran, 1.86 mL, 1.86 mmol), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 M hydrochloric acid on an ice bath until pH became 7 or lower, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-[3,5-bis(trifluoromethyl)phenyl]-1-propanol (165 mg, 49%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([OH:19])([CH2:16][CH:17]=[CH2:18])[C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[H-].[Na+].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25]>CN(C=O)C.O>[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:19][C:3]([C:2]([F:1])([F:20])[F:21])([C:4]#[C:5][Si:6]([CH:13]([CH3:14])[CH3:15])([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])[CH2:16][CH:17]=[CH2:18])=[O:32])=[CH:34][CH:35]=1)([O-:26])=[O:25]
Reactant: C=CCC(O)(C#C[Si](C(C)C)(C(C)C)C(C)C)C(F)(F)F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#C[Si](C(C)C)(C(C)C)C(C)C)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.67 h
Yield: 96.5 %

Procedure:
To a 0° C. solution of crude 3-(trifluoromethyl)-1-(triisopropylsilyl)hex-5-en-1-yn-3-ol from Step 1 (242 mg, 0.755 mmol) in DMF (2 mL) was added NaH (60% disp., 32 mg, 0.793 mmol) in two portions. The mixture was allowed to reach room temperature and stirred for 40 min. A solution of 4-nitrobenzoyl chloride (147 mg, 0.793 mmol) in DMF (1 mL) was added dropwise. After 1.5 h, the mixture was poured in H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O (3×) and brine, dried (Na2SO4) and concentrated, affording the title compound (342 mg).