Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28](=[O:30])[CH3:29]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:27][C:28](=[O:30])[CH3:29])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CC(=O)CCl
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (prepared according to Example 16, Steps A-D; 10.07 g, 31.0 mmol) in DMF (150 mL) at ambient temperature was added cesium carbonate (30.3 g, 92.9 mmol), followed by chloroacetone (5.2 mL, 65.1 mmol). The resulting mixture was vigorously stirred at ambient temperature for 1 hr, then diluted with water (1000 mL). After stirring for 1 hr, the precipitate that formed was collected by filtration, washed with water, and air-dried. This material was dissolved in boiling ethanol (150 mL), and then of water (80 mL) was added. The resulting mixture was cooled at 2° C. for 16 hr. The crystals that formed were collected by filtration, washed with 50/50 water/ethanol, and dried under vacuum to afford the title compound as a light orange powder (8.13 g, 69%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:19])([F:20])[F:18])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2C(F)(F)F)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2C(F)(F)F)n1
Yield: 70.7 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g, 5.12 mmol) and phenyl chloroformate (1.95 mL, 15.4 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (1.46 g, 3.62 mmol, 71%). 1H NMR (300 MHz, DMSO-d6) δ 10.20 (br s, 1H), 7.92 (d, 1H), 7.85 (t, 1H), 7.74 (t, 1H), 7.54 (d, 1H), 7.38-7.36 (m, 2H), 7.23 (t, 1H), 7.09 (br s, 2H), 6.32 (s, 1H), 1.25 (s, 9H); LC-MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:31][CH:27]3[CH2:30][CH2:29][CH2:28]3)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCC1
Product: N#CC(=C(Nc1ccc2c(c1)OCO2)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 29.1 %

Procedure:
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.29 g, 0.7 mmol) was stirred in cyclobutylamine (0.6 ml 7.0 mmol) for 17 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue was crystallised from ethyl acetate to give 88 mg (29%) of the title compound. Mp 189.5° C. 1H NMR (200 MHz, CDCl3): δ=1.6 (m, 2H), 1.75 (m, 2H), 2.05 (m, 2H), 3.80 (m, 1H), 6.02 (s, 2H), 6.5 (m, 2H), 6.79 (d, 2H), 7.50 (dt, 2H), 7.83 (dt, 2H). Analysis: calc. for C20H18ClN3O4S: C, 55.62%; H, 4.20%; N, 9.73%; Found: C, 55.59%; H, 4.21%; N, 9.59%.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:24][CH2:23]1)[CH3:21]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
The title compound was prepared from 4-bromo-1-(benzenesulfonyl)-1H-indole and 4-ethylpiperazine according to Method 1 to afford 129 mg (48%) of a white solid: 1H NMR (CD3OD) δ 7.94-6.81 (m, 10H), 3.69-3.62 (m, 4H), 2.34-3.26 (partly hidden) (m, 4H), 3.14-3.04 (m, 2H), 1.40 (t, J=7 Hz, 3H); MS (ESI) 370.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[S:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: COc1cc(F)c(C=O)cc1OC
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2s1
Temperature: 60 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 2-fluoro-4,5-dimethoxybenzaldehyde (1.10 g, 6 mmol) in DMF (50 mL) was added methyl 2-mercaptoacetate (0.58 mL, 6.6 mmol) and potassium carbonate (2.48 g, 18 mmol). The resulting mixture was then heated at 60° C. for 15 hours. The DMF was removed via rotary evaporation and the residue was diluted with water and extracted with DCM. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to afford methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate as a light yellow solid (1.0 g, 67%). LC-MS (ES-API); rt 8.48 min; m/z calculated for C12H12O4S [M+Na]+ 275.0, found 275.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:4]=1.[C:22]1([N:28]2[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C=O)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:31]3[CH:30]=[N:29][N:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 3-(aminomethyl)-7-fluoro-1-(2-fluorophenyl)quinolin-4(1H)-one (intermediate H) (50 mg, 0.175 mmol), 1-phenyl-1H-pyrazole-4-carboxylic acid (66 mg, 0.349 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (112 mg, 0.24 mmol), triethylamine (53 mg, 0.524 mmol), and DMF (3 mL) was stirred at room temperature overnight. The crude material was purified by flash chromatography (12 g silica gel eluting with 100% hexanes ramped to 70% ethyl acetate in hexanes). The product 1-phenyl-1H-pyrazole-4-carboxylic acid [7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-amide (46 mg, 58%) was obtained as an off-white solid. MS calcd. for C22H14ClF2N3O2 [(M+H)+] 426.1, obsd. 426.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26]1([CH:29]=[CH:30]B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:30]=[CH:29][CH:26]2[CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: CC1(C)OB(C=CC2CC2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CC2CC2)Cc2ccccc2C1
Yield: 47.9 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (600 mg, 1.34 mmol) and 2-(2-cyclopropyl-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.11 mL, 5.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 285 mg, 0.13 mmol) and 2M aqueous solution of K2SO4 (2.68 mL, 5.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (137) as white solid (250 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:16])[CH2:13][CH2:14]Cl)[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[C:8](=[O:21])[NH:7][C:6]=2[CH:22]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:16])[CH2:13][CH2:14][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[CH3:23])[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[C:8](=[O:21])[NH:7][C:6]=2[CH:22]=1
Reactant: O=C1Nc2cc(Cl)ccc2N(C(=O)CCCl)c2ccccc21
Reactant: CC1CCCCN1
Solvent: CC(C)O
Product: CC1CCCCN1CCC(=O)N1c2ccc(Cl)cc2NC(=O)c2ccccc21

Procedure:
11.5 gm (0.034 mol) of 8-chloro-5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (m.p. 235°-237° C.) and 16.2 gm (0.16 mol) of 2-methyl-piperidine were refluxed in 100 ml of isopropanol for 1 hour. The reaction mixture was then evaporated in vacuo, the residue was dissolved in chloroform, the solution was washed with sodium hydroxide, and the organic solvent was distilled off in vacuo. The residue was recrystallized from xylene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][C:39]([NH:42][CH2:43][CH2:44][CH2:45][NH2:46])([CH3:41])[CH3:40]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH2:45][CH2:44][CH2:43][NH:42][C:39]([CH3:41])([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)NCCCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCCNC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1,1-dimethylethyl)-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) 1.09 (m, 9H), 1.70 (m, 2H), 2.33 (m, 3H), 2.47 (m, 1H), 2.66 (m, 1H), 3.13 (m, 1H), 3.47 (m, 1H), 6.36 (d, J=8.8 Hz, 1H), 7.10 (m, 1H), 7.23 (m, 2H), 7.47 (m, 2H), 7.58 (m, 2H), 8.04 (m, 1H), 8.13 (d, J=7.6 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[S:20][C:21]4[C:22]([N:27]=3)=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:12]=2[O:11][CH:10]=1)(C)(C)C.[ClH:29]>C(Cl)Cl.C(OCC)C>[ClH:29].[S:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:27]=[C:19]1[O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([CH2:8][NH2:7])=[CH:10][O:11][C:12]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 130 %

Procedure:
To a solution of 2 [6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-ylmethyl]-carbamic acid tert-butyl ester (0.10 g, 0.25 mmol) in DCM (1.2 mL) was added 2 M HCl in diethyl ether (0.38 mL). The reaction was stirred (rt, 16 h) before additional HCl (0.38 mL) was added. The reaction was stirred (rt, 24 h) and concentrated to provide the title compound as a white solid (98 mg, 130%). Additional mass is likely due to retained HCl and/or solvent. MS (ESI): mass calcd. for C15H11N3O2S, 297.06; m/z found, 298.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g (34.7 mmol) of 4-(isoquinolin-6-yloxy)-cyclohexylamine (15) were dissolved in 100 ml of dichloromethane/pyridine (4:1). At 0° C. a solution of 3.27 g (41.6 mmol) of acetyl chloride in 10 ml of dichloromethane was added and the reaction mixture was stirred at room temperature. After 2 h, the solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. After washing twice with 2 N HCl, the product was transferred to the aqueous phase. The HCl-layers were adjusted to alkaline pH by addition of solid NaOH and extracted three times with dichloromethane. Drying the organic layers with magnesium sulfate and evaporation of the solvent gave 7.69 g of the crude product. After silica gel chromatography 4.48 g of the title compound were isolated. Rt=0.87 min (Method A). Detected mass: 285.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(O)CC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:21][CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(=O)NCCN
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
4,6-Dichloro-2-phenylpyrimidine (3) (5.59 g), N-acetylethylenediamine (2.79 g) and N,N-diisopropylethylamine (3.53 g) were added to propan-1-ol (50 ml). A calcium drying tube was fitted and the resulting suspension heated to reflux for 34 hrs, then left to cool to ambient temperature. The resulting solution was evaporated in vacuo onto silica gel (40 g) and purified by flash chromatography eluting with ethyl acetate then a mixture of ethyl acetate and methanol (10:1 v/v) to furnish the title compound (6.79 g).
Reaction SMILES: C1COCC1.[C:6](#[N:8])[CH3:7].C([Li])CCC.[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20]C)=O>CC(O)=O>[CH3:14][C:15]1[CH:16]=[C:17]([C:18](=[O:20])[CH2:7][C:6]#[N:8])[CH:22]=[CH:23][N:24]=1
Reactant: CC#N
Reactant: COC(=O)c1ccnc(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CC#N)ccn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 50 ml flask was added 8 ml of THF, acetonitrile (156 μl, 2.98 mmole), the mixture was cooled to −78° C. and then n-butyllithium (1191 μl, 2.98 mmole, 2.5 m in hexanes) was added. The reaction was stirred for 30 minutes at which time methyl 2-methylisonicotinate 16.1.B (150 mg, 0.99 mmoles) was added as a 2 ml THF solution. After 2 hour at −78° C., 500 μL of AcOH was added and the reaction was warmed to room temperature. The solvent was removed and the crude was purified on a silica gel column (eluting with 2% MeOH in DCM) to give 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile 16.1.C as a light orange solid (170 mg 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#N)[CH:24]=1)=[NH:22]>CO>[C:21]([C:23]1[CH:24]=[C:25]([C:29]2[NH:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:11]=2)[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: CO
Product: N#Cc1cccc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)CN2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a solution of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine (500 mg) in methanol (10 mL) was added 3-cyanobenzeneimidic acid methyl ester (792 mg), and the mixture was stirred at room temperature for 18 hrs. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate (30 mL), washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=3:1→2:1) to give the objective compound (370 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH:22]1(CCCN)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:12]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:3][CH2:2][CH3:1])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: NCCCC1CCCCC1
Product: CCCN(c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1)C1CCCCC1
Yield: 82 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and cyclohexylpropylamine (Chembridge), the title compound was obtained as a beige solid in 82% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]([CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:8][CH2:7][CH2:6][C@H:5]([O:4][CH2:3][CH2:2][O:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:40])=[O:39]
Reactant: OCCO[C@@H](CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCO[C@@H](CCOS(C)(=O)=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
(S)-3-(2-hydroxyethoxy)-4-(tripenylmethoxy)-1-butanol (500 g, 1.27 mole) was dissolved in 4.8 L of CH2Cl2, was cooled to 0° C. under N2, and triethylamine (386.4 g, 532 mL, 3.81 mole, 3.0 eq.) was added. Methanesulfonyl chloride (396.3 g, 268 mL, 3.46 mole, 2.7 eq.) was then added dropwise over 30 minutes at <5° C. The resultant reaction mixture was stirred at 0° to 5° C. for 1-2 hours and was monitored by HPLC. The reaction mixture was diluted with additional CH2Cl2 and was washed twice with 2 L of water and 2 L of an aqueous saturated solution of ammonium chloride. The aqueous layers were back-extracted with 1 L of CH2Cl2 and the combined organic layer was dried (MgSO4) and evaporated in vacuo to give a crude solid that was recrystallized from 1/1 heptane/ethyl acetate to give 615 g (88%) of (S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate in three crops as a solid. NMR. MS.
Reaction SMILES: Br[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CCN(C(C)C)C(C)C>ClC1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[C:18]([C:19]([O:21][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:20])=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=1
Reactant: O=C1C=C(Br)C2CCC1C2
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C

Procedure:
A mixture of 27 g of a 6.2% solution of 4-bromobicyclo[3.2.1]oct-3-en-2-one (Preparation Example P1) in chlorobenzene, 110 mg of ZnCl2, 2.34 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid and 1.2 g of Hünig's base is stirred at room temperature under a nitrogen atmosphere until a dark-brown solution is formed. The reaction mixture is then maintained under moderate reflux for 19 hours in an oil bath, with stirring. The mixture is then divided into 2 portions. To one portion there are added a further 1.12 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid, 0.06 g of ZnCl2 and 0.6 g of Hünig's base. The reaction mixture is then maintained under moderate reflux for 12 hours in an oil bath, with stirring. The solution is then washed twice with 0.1M hydrochloric acid (20 ml each time) and twice with water (20 ml each time). After drying the organic solution using magnesium sulfate and concentrating in vacuo, 3.9 g of 4-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one are obtained in the form of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH3:21][S:22][CH2:23]CCl>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:21][S:22][CH3:23])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CSCCCl
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene is treated in 20 ml. dimethylformamide under nitrogen at 20°-25° with 1.14 g. sodium borohydride. After 1 hour 10 ml. of methylthioethylchloride is added and the mixture stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column, then evaporated to dryness to afford 1-amino-2-nitro-4-methylthioethylthiobenzene.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>O>[CH2:30]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:29]=[CH2:28]
Reactant: CC(=NO)c1ccc(NC(=O)NCC(=O)Oc2ccccc2)cc1
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)Oc2ccccc2)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-phenoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-allyloxyiminoethyl)phenyl]-N'-phenoxycarbonylmethylurea.