Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=C(F)C=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]23)[CH:17]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O.[OH-].[Ba+2].[OH-]>COCCOC.C(OCC)(=O)C.O>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]23)[CH:17]=1
Reactant: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCNC2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCNC3)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-butyl (±)Cis-bromo-4-oxo-1,2,3,4,7b, 10,11,11 a-octahydro[1,4]diazepino[6,7,1-hi]pyrido[4,3-b]indol-9(8H)-carboxylate from EXAMPLE 70, Part E (150 mg, 0.356 mmol), 2,4-dichlorophenylboronic acid (82 mg, 0.430 mmol) and barium hydroxide (170 mg, 0.540 mmol) were dissolved in DME (7 mL) and water (4 mL), and degassed for 10 minutes under nitrogen. Tetrakis (triphenylphosphine)palladium (0) (10 mg, 0.007 mmol) was added and the reaction was heated to 90° C. for 13 h. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (13% ethyl acetate, hexanes).). Fractions were collected, concentrated to a solid, then dissolved in 20% TFA/CHCl3 and stirred for 1 hour. The reaction solution was cooled to 0° C. in an ice bath, and basified to pH=10 with concentrated NH4OH. This was extracted with CHCl3 (3×15 ml), organics collected, dried over MgSO4 and concentrated under reduced pressure to give to give the title compound. 1H NMR (CDCl3, 300 MHz): δ 7.52 (d, 1H, J=1.8 Hz), 7.44 (d, 1H, J=1.8 Hz), 7.26-7.20 (m, 2H), 6.45 (s, 1H), 4.34 (t, 2H, J=9.2 Hz), 4.14-4.06 (m, 2H), 3.18-2.95 (m, 3H), 2.88-2.75 (m, 3H), 2.14 (s-br, 1H), 1.96-1.79 (m, 2H) ppm.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11](C(OCC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].CO.[C:26]([OH:29])(=O)C.[CH:30]([NH2:32])=[NH:31]>>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[C:26](=[O:29])[NH:32][CH:30]=[N:31][C:11]=2[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Yield: 90 %

Procedure:
1-Benzyl-3-ethoxycarbonyl-4-piperidone hydrochloride (12.89 g, 43.3 mmol) was suspended in a sodium methoxide solution in methanol (25% wt/wt, 50 mL, 216.2 mmol) and formamidine acetate (5.4 g, 51.9 mmol) was added to the mixture. The reaction mixture was refluxed until all of the starting material was consumed (2 h). The methanol was removed under vacuum, and the resulting white solid was dissolved in a 3:1 mixture of chloroform: isopropanol. The mixture was washed with water and brine, dried over Na2SO4, filtered and evaporated to give the desired product as a white solid (9.4 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(OCC)C>[O:20]([C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccccc1
Yield: 24 %

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 13.2 g. of phenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. ethyl ether. The ethereal solution was extracted with 2×50 ml. of 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallizations from cyclohexane gave analytically pure product melting at 101°-104° C. The yield was 24% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([CH:11]2[CH2:13][CH2:12]2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=[O:15].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([CH:11]2[CH2:12][CH2:13]2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:15]
Reactant: N#Cc1cc(C2CC2)c(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 838.7 %

Procedure:
To a stirred mixture of compound 2,6-dichloro-5-cyclopropylnicotinonitrile (1.10 g, 5.16 mmol) and K2CO3 (351 mg, 2.58 mmol) in DMSO (10 mL) was added 30% H2O2 (1.90 mL, 15.5 mmol). The mixture was stirred for 2 hrs at rt. Then the mixture was poured into water and extracted with EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to give compound 2,6-dichloro-5-cyclopropylnicotinamide (5 g, 70%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.69 (s, 1H), 6.70 (s, 1H), 6.20 (s, 1H), 2.08 (m, 1H), 1.18 (m, 2H), 0.69 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:22][C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([NH:30][C:31]2[CH:39]=[C:38]3[C:34]([CH2:35][CH2:36][N:37]3C(OC(C)(C)C)=O)=[CH:33][CH:32]=2)=[O:29])=[CH:13][CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[NH:37]1[C:38]2[C:34](=[CH:33][CH:32]=[C:31]([NH:30][C:28]([C:24]3[S:25][CH:26]=[CH:27][C:23]=3[NH:22][CH2:21][C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:11]=[CH:12][CH:13]=3)=[O:29])[CH:39]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(NC(=O)c3sccc3NCc3ccnc4ccccc34)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)NCC2)c1sccc1NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of TFA/CH2Cl2 (3 mL, 1:1, v:v) was added tert-butyl 6-({[3-[(quinolin-4-ylmethyl)amino]thien-2-yl]carbonyl}amino)indoline-1-carboxylate (40 mg, 0.08 mmol) and the resulting mixture was stirred at rt. After 1 h, the solution was neutralized with 3N NaOH and diluted with EtOAc. The aqueous phase was removed and the organic phase was washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to yield N-2,3-dihydro-1H-indol-6-yl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide as a yellow solid. MS (ES+): m/z 401 [M+1]. 1H NMR (CDCl3, 400 MHz): δ3.00 (t, J=8.4 Hz, 2H), 3.58 (t, J=8.4 Hz, 2H), 4.99 (d, J=6.4 Hz, 2H), 6.54 (d, J=5.6 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 7.46 (d, J=4.4 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 8.03 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.85 (d, J=4.4 Hz, 1H).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.Br[C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]2[C:26]=1[CH2:27][N:28]([CH3:38])[C:29]2=[O:37].CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1.[CH3:57][C:58]1([CH3:78])[O:62][C@@H:61]([CH2:63][N:64]2[CH:68]=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:66]=[N:65]2)[CH2:60][O:59]1>>[CH3:57][C:58]1([CH3:78])[O:62][C@@H:61]([CH2:63][N:64]2[CH:68]=[C:67]([C:25]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]4[C:26]=3[CH2:27][N:28]([CH3:38])[C:29]4=[O:37])[CH:66]=[N:65]2)[CH2:60][O:59]1
Reactant: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CN1Cc2c(-c3cnn(C[C@H]4COC(C)(C)O4)c3)ccc([N+](=O)[O-])c2C1=O
Yield: 99 %

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with Compound 1L and Compound 3E with 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 5E) to afford 1.96 g of the desired product (99%). 1H NMR (400 MHz, CDCl3) δ 7.79-7.85 (m, 2H), 7.74-7.80 (m, 1H), 7.65-7.73 (m, 1H), 4.46-4.58 (m, 3H), 4.36 (dd, J=5.05, 13.39 Hz, 2H), 4.14 (dd, J=6.44, 8.72 Hz, 1H), 3.83 (dd, J=6.06, 8.59 Hz, 1H), 3.24 (s, 3H), 1.34-1.44 (m, 6H). MS (ESI): m/z 373.16 [M+H]+. UPLC: tR=1.16 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].C([O-])(=O)C.[Li+].Cl>CO.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])([CH3:13])[C:16]([F:18])([F:17])[F:15])[CH:6]=[CH:5]2
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(O)(c1ccc2cc(Br)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a DMF (25 ml) solution of 1-(6-bromo-2-naphthyl)ethanone (2.5 g, 10.0 mmol, Tetrahedron Letters (2001), 42(2), 265-266), trifluoromethyltrimethylsilane (2.14 g, 15.1 mmol) and lithium acetate (33.1 mg, 0.5 mmol) were added and the mixture was stirred for 12 hrs at room temperature. Then, the reaction was partitioned with sodium acetate aqueous solution and ethylacetate. The organic layer was dried over sodium sulfate and filtered. Then, evaporation gave the crude residue which was treated with hydrogen chloride and methanol with stirring for 5 hrs. Then, evaporation gave the crude residue which was purified through silica gel column chromatography, eluting with hexane:ethyl acetate (5:1), to give the title compound as colorless oil in 83% yield. 1H NMR (300 MHz, CDCl3) 2.50 (1H, s), 7.58 (1H, d, J=8.8 Hz), 771-7.81 (3H, m), 8.04 (2H, d, J=8.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24](=O)[NH:23]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24](=[S:44])[NH:23]1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Yield: 67 %

Procedure:
In a manner analogous to that described in Example 2b), the reaction of (R)-5-[2,4-difluoro-5-(6-trifluoromethyl-benzo oxazol-2-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (163 mg, 332 μmol) with Lawesson's reagent (145 mg, 359 μmol) yielded the title compound (113 mg, 67% yield as a white solid. MS (ISP): m/z=507.1 [M+H]+.
Reaction SMILES: CC1[O:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3NCCC=2N=1.S(Cl)(Cl)=O.[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.C([N:38]([CH2:41][CH3:42])CC)C>C1(C)C=CC=CC=1.ClCCl>[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[N:26]([C:10]([C:9]3[CH:12]=[CH:13][C:42]([C:41]#[N:38])=[C:15]([CH3:14])[CH:8]=3)=[O:11])[CH2:25][C:24]=2[CH:23]=[N:22]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2
Reactant: Cc1nc2c(o1)-c1ccccc1NCC2
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
A mixture of 4-cyano-3-methyl-benzoic acid from Example E6 (753 mg, 4.7 mmol) and thionyl chloride (1.02 ml, 14.0 mmol) in toluene (50 ml) was heated at reflux for 2 h. After cooling at room temperature, solvents were re-moved in vacuo and azeotroped with toluene. The residue was redissolved in dichloromethane (45 ml) and a solution of 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (11.0 g, 4.7 mmol) in dichloromethane (5 ml) and triethylamine (1.3 ml, 9.3 mmol) was added slowly. The mixture was stirred at room temperature for 20 h, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (1.42 g, 85%).
Reaction SMILES: [C:1]1(C(CCCC)CN)[CH:6]=CC=C[CH:2]=1.Cl.[C:15]1([CH:21]([CH2:50]C(C)C)[CH2:22][N:23]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH2:41][C:42](=[CH:46][C:47]([OH:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=2[Cl:35])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:35].[C:15]1([CH:21]([CH2:50][CH2:2][CH2:1][CH3:6])[CH2:22][N:23]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH2:41][C:42](=[CH:46][C:47]([OH:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[C:26]=2[Cl:35])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCC(CN)c1ccccc1
Reactant: CC(C)CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Agent: Cl
Product: CCCCC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1

Procedure:
The titled compound was prepared from 2-phenylhexylamine (J. Chem. Soc. Perk. Trans. 1: Organic and Biorganic Chemistry (1976), (1), 33-8) in the same manner as the preparation of N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine, hydrochloride, Example 189e-h. MS (ESI) 562 (MH+)
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>[Fe].CO>[CH2:3]([S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCSCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCSCc1ccc(N)cc1
Temperature: 50 °C
Yield: 95.2 %

Procedure:
Ammonium chloride (152.9 g, 2.858 mol), 1 (225.0 g, 0.572 mol), water (2.8 L), methanol (3.8 L) were combined and mechanically stirred at 50° C., then powdered iron (95.9 g, 1.715 mol) was added portionwise over ten minutes. The suspension was vigorously stirred at reflux for 2.5 hours, then hot filtered through a celite pad. The pad was rinsed with water (3×700 mL) and CH2Cl2 (5×700 mL). The aqueous layer was extracted with CH2Cl2 (3×1 L), then concentrated to remove methanol and again extracted with CH2Cl2 (3×500 ml). The combined organics were washed with water (2×3 L), dried (Na2SO4), filtered, and spin-evaporated to give 198.1 g (95.3% yield) of 2 as a pale yellow solid. TLC (7:1 hexanes/EtOAc) indicated a single spot. This lot was combined with that of a 100 mmol run to give a total of 231 g of 2 (94.3% yield) which was suitable for further transformation.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:17][CH3:18])=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:17][CH3:18])=[N:10][CH:11]=[C:12]([C:14]([O:16][CH3:19])=[O:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ncc(C(=O)O)cc1Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cnc(OC)c(Cc2ccccc2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 2.1 g of 3-benzyl-2-methoxypyridine-5-carboxylic acid and 2.9 g of potassium carbonate was suspended in 40 ml of N,N-dimethylformamide. 1.1 ml of methyl iodide was added-thereto at room temperature under stirring. After stirring for 40 minutes, water was added thereto and extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography using 11-14% ethyl acetate/hexane as an eluent for separation and purification, to give 2.2 g of the target compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])N.[N+:16](C1C=C(B(O)O)C=CC=1)([O-])=O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:3]([C:1]#[N:2])[C:4]([NH2:16])=[O:6])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Product: N#CC(C(N)=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 79 %

Procedure:
A 500-mL round bottomed flask under N2 equipped with overhead stirrer, a Dean-Stark trap and condenser, thermocouple was charged with cyanoacetic acid (28.04 g, 0.33 mol), 3-chloro-4-fluoroaniline (40.0 g, 0.28 mol), 3-nitrophenylboronic acid (2.28 g, 0.014 mol) and toluene (200 mL). The mixture was heated to reflux and water collected in the Dean-Stark trap. After 5.5 hours, thin layer chromatography (TLC) indicated complete consumption of the aniline. The reaction mixture was cooled to room temperature (RT) forming a pink suspension. The solids were isolated by filtration, washed with MTBE (2×200 mL) and dried to afford (3-chloro-4-fluorophenyl)-2-cyanoacetamide as a pale pink solid (46.40 g, 79% yield, 96.7% by GC-MS). 1H NMR (300 MHz, DMSO-d6): 10.4 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.5-7.3 (m, 2H), 3.92 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([Cl:22])=[C:20](Cl)[N:19]=[C:18](Cl)[C:17]=2Cl)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(=O)C.[Na+].CO.[H][H]>[Pd].C(O)C>[ClH:22].[N:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cl
Product: c1cc(NCC2CCNCC2)ccn1
Reaction time: 7 h

Procedure:
A suspension of 1-t-butoxycarbonyl-4-(2,3,5,6-tetrachloropyridin-4-ylaminomethyl)piperidine (18.5 g, 43.1 mmol), sodium acetate (21.2 g, 259 mmol) and 5% palladium on activated carbon (9.17 g, 4.31 mmol) in ethanol (340 mL)/methanol (170 mL) is stirred rapidly under 1 atmosphere of hydrogen for 20 hours. After the atmosphere of hydrogen is replaced with argon the mixture is filtered through a bed of Celite™ washing with methanol. The mixture is concentrated in vacuo and the residue is taken into chloroform and saturated sodium bicarbonate solution. The phases are separated and the aqueous phase is extracted into chloroform (×2). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. The residue is taken into methanol (1.20 L) and hydrogen chloride gas is passed through the solution maintaining <20° C. The mixture is kept at this temperature for 7 hours before it is concentrated in vacuo giving 4-(pyridin-4-ylaminomethyl)piperidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C([Mg]Br)(C)C.[CH:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22])([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:21]([C:20]2[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:19]=2[CH:16]([CH3:18])[CH3:17])[OH:22])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1ncc(I)c(Cl)n1
Reactant: COc1cc(C=O)c(C(C)C)cc1OC
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(C(O)c2cnc(SC)nc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methylsulfanyl-pyrimidine (1.10 g, 3.9 mmol) in 20 mL THF at −40° C. was added isopropyl magnesium bromide (2.3 mL, 2 M in THF) ) over 5 minutes. After 30 minutes, 2-isopropyl-4,5-dimethoxy-benzaldehyde from step 3 (1.04 g, 4.6 mmol) was added and the solution was warmed to room temperature. The mixture was quenched by the addition of brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (ethyl acetate) afforded (4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-(2-isopropyl-4,5-dimethoxy-phenyl)-methanol (1.168 g, 82%) as a light yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:7]=1)=[O:5].[CH3:24][CH2:25][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:7]=1)(=[O:5])[CH2:24][CH3:25]
Reactant: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of N-methoxy-N-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (1.20 g, 3.52 mmol) in THF (20 mL) was added EtMgBr (1.0 M in THF, 7.04 mL, 7.04 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was warmed to room temperature, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (767 mg, 74% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.06 (3H, t, J=7.2 Hz), 2.99 (2H, q, J=7.2 Hz), 6.73 (1H, d, J=8.3 Hz), 7.79-7.88 (2H, m), 8.06-8.17 (2H, m), 8.97 (1H, d, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCc1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(CCCBr)c1
Yield: 70.9 %

Procedure:
Compound 25-1 (1.00 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (1.71 g) and N-bromosuccinimide (1.15 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (970 mg) as a colorless oil.