Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[CH:3][CH:2]=1.[Br:16][CH2:17][CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28](=[O:30])[CH3:29])[CH2:20]1.O1CCOCC1.O1CCCC1>CO>[Br-:16].[C:28]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:19]([CH2:18][CH2:17][N+:1]2[CH:6]=[CH:5][C:4]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][CH:11]=[CH:10]4)=[CH:3][CH:2]=2)[CH2:20]1)(=[O:30])[CH3:29]
Reactant: c1cc(-c2ccc3[nH]ccc3c2)ccn1
Reactant: CC(=O)N1C[C@@H](CCBr)c2ccccc21
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(=O)N1C[C@@H](CC[n+]2ccc(-c3ccc4[nH]ccc4c3)cc2)c2ccccc21
Product: [Br-]
Temperature: 80 °C
Yield: 66.8 %

Procedure:
A mixture of 5-(pyridin-4-yl)-1H-indole (17.2 g, 0.089 mol), 1-[(S)-3-(2-bromoethyl)-2,3-dihydro-1H-indol-1-yl]-ethanone (28.5 g, 0.11 mol), 1,4-dioxane (900 mL), tetrahydrofuran (150 mL) and methanol (100 mL) was heated under reflux at approximately 80° C. for 68 h. The mixture was cooled, and the solid formed was collected by filtration and washed with tetrahydrofuran. The compound was dried in vacuo to give 1-[2-((S)-1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-4-(1H-indol-5-yl)pyridinium bromide (27.5 g, 64%), which was suspended in methanol (900 mL) and cooled (5° C.). To this mixture was added sodium borohydride (6.75 g, 0.18 mol) over a period of 20 min. The resulting mixture was stirred at 10° C. for 1 h and concentrated to about 200 mL. The mixture was poured onto a mixture of brine (750 mL) and 28% aqueous sodium hydroxide (20 mL), and the aqueous phase was extracted with a mixture of ethyl acetate and tetrahydrofuran. The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/tetrahydrofuran/triethylamine 70:25:5) to give 1-((S)-3-{2-[4-(1H-indol-5-yl)-3,6-dihydro-2H-piperidin-1-yl]ethyl}-2,3-dihydro-1H-indol-1-yl)-ethanone (20.5 g, 85%). This compound (8.0 g, 0.02 mol) was dissolved in 1-propanol (220 mL) and heated to 60° C. To this mixture was added 28% aqueous sodium hydroxide, and the resulting mixture was boiled under reflux for 7 h. The mixture was cooled and poured onto brine. The aqueous phase was extracted with a mixture of ethyl acetate and tetrahydrofuran, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was combined with a residue coming from another experiment starting from 1 g of 1-((S)-3-{2-[4-(1H-indol-5-yl)-3,6-dihydro-2H-piperidin-1-yl]ethyl}-2,3-dihydro-1H-indol-1-yl)-ethanone. The combined residue was purified by flash chromatography (ethyl acetate/triethylamine 95:5) to give the title compound (4.95 g).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[CH3:13][O:10][C:9]([CH:8]([OH:12])[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
L-3-Phenyllactic acid (5 g, 30 mmol) was dissolved in 25 mL of dimethylformamide and cesium carbonate (9.94 g, 30.5 mmol) was added. After the evolution of gas ceased, methyl iodide (8.52 g, 60 mmol) was added and the mixture was stirred for 18 hours at room temperature. Water was then added and the mixture extracted with ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a colorless oil (5.4 g, 100% yield).
Reaction SMILES: [OH:1][C@H:2]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[Si:14](OS(C(F)(F)F)(=O)=O)([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].CCN(CC)CC>C(Cl)Cl>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:1][C@H:2]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1)([CH3:17])[CH3:16]
Reactant: O=C1CCC[C@@H](O)c2ncccc21
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CCCC(=O)c2cccnc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 1L round-bottomed flask was (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (19.14 g, 108 mmol) (azeotroped with dry benzene) in CH2Cl2 (300 mL) to give a tan solution. After cooling to 0° C., TIPS-OTf (29.3 mL, 108 mmol) and Et3N (30.1 mL, 216 mmol) were added via syringe, and the mixture was stirred at 0° C. for 1h. LCMS indicated complete conversion. Volatiles were stripped off and the residue was partitioned between NaHCO3 solution and EtOAc. The layers were separated and the organic layer was washed with brine, dried and concentrated to a tan oil (37 g). It was purified by FCC up to 20% EtOAc/hexane to afford the product as a white solid (26.3 g, 73% for two steps). MS(ESI)[M+H+]=334.37.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1.[NH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:9]=[C:5]([CH:4]=[CH:3][CH2:2][N:17]3[C:21](=[O:22])[CH2:20][CH2:19][C:18]3=[O:23])[S:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Reactant: O=C1CCC(=O)N1
Product: O=C1CCC(=O)N1CC=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
The compound was prepared analogously to example 3e) from 100 mg (0.39 mmol) of 2-(3-chloropropenyl)-4-(4-fluorophenyl)thiazole and 46.8 mg (0.47 mmol) of pyrrolidine-2,5-dione. Yield: 24 mg (17%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[CH2:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: C1CNCCN1
Reactant: CC(C)CNS(=O)(=O)c1ccc(F)cc1
Solvent: O
Product: CC(C)CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 150 °C
Yield: 89.5 %

Procedure:
A microwave vial was charged with 4-fluoro-N-isobutyl-benzenesulfonamide (1.0 g, 4.32 mmol), piperazine (1.86 g, 21.60 mmol) and water (20 mL) and heated at 150° C. for 1 hour using a microwave reactor. The solid from the reaction mixture was collected by filtration, washed with water and dried to give N-isobutyl-4-piperazin-1-yl-benzenesulfonamide (1.15 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.33 (t, J=6.5 Hz, 1H), 3.32-3.25 (m, 4H), 3.05-2.99 (m, 4H), 2.73 (t, J=6.6 Hz, 2H), 1.78-1.65 (m, 1H), 0.87 (d, J=6.7 Hz, 7H). LCMS (m/z, Method A) ES+ 298.2 [M+1]+.
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:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].Cl.Cl.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH2:48]>C(Cl)Cl.C(N(CC)CC)C.CCOC(C)=O.[OH-].[Na+]>[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]([NH:48][CH2:47][C:43]3[NH:42][CH:46]=[CH:45][N:44]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[8-(2,6-Difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.084 g, 0.154 mmol) and (1H-imidazol-2-ylmethyl)amine dihydrochloride (0.039 g, 0.23 mmol) were dissolved in CH2Cl2 (5 mL) and triethylamine (0.7 mL). The resulting mixture was stirred under argon at room temperature overnight. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and 1 N NaOH. The organic phase was washed with brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 6:1:0.05 CH2Cl2:isopropanol:NH4OH. The material isolated was not pure, and was rechromatographed on silica gel (20 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a white amorphous solid. mp (dec) 185-190° C. LC-MS m/z 578 (M+H)+, 1.76 min (ret time).
Reaction SMILES: CC([NH2:9])C1C=CC=CC=1.C(OS(C(C1C=CC=CC=1)C1C=CC=CC=1)=O)(=O)C.[CH:29]([S:42]([CH2:44][C:45]([OH:47])=[O:46])=[O:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.S(OC)(OC)(=O)=O.N>>[CH:33]1[CH:32]=[CH:31][C:30]([CH:29]([S+:42]([O-:43])[CH2:44][C:45]([NH2:9])=[O:47])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:35][CH:34]=1.[CH:39]1[CH:40]=[CH:41][C:36]([CH:29]([S:42]([CH2:44][C:45]([OH:47])=[O:46])=[O:43])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:37][CH:38]=1
Reactant: CC(N)c1ccccc1
Agent: CC(=O)OS(=O)C(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Solvent: COS(=O)(=O)OC
Product: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1

Procedure:
The (−)-α-methylbenzylamine-(−)-benzhydrylsulphinyl acetate is then converted to (−)-benzhydrylsulphinylacetic acid by acid hydrolysis. The latter is esterified in the presence of dimethyl sulphate and then converted to amide in the presence of ammonia (gas). The (−) or I (laevorotatory) enantiomer of modafinil is obtained through this process with an overall yield of 5.7% in relation to the (±) modafinil acid, calculated on the basis of the yields corresponding to each stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:25]3[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[O:17])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.094 g (0.29 mmol) of 3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg (0.29 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with DCM, and DCM/MeOH (20/1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][N:46]([CH3:55])[C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][N:46]([CH3:55])[C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:49][CH:48]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(N(C)C)cc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 4-dimethylaminobenzylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(4-dimethylaminobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 2.98 min, MH+ 427.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(O)(C)C>[ClH:1].[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]1=2
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: C1COCCN1
Solvent: CC(C)O
Product: CN1C(=O)c2ccccc2N(C(=O)CCN2CCOCC2)c2ccccc21
Product: Cl

Procedure:
6.3 gm (0.02 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 10 gm (0.11 mol) of morpholine were refluxed in 200 ml of isopropanol for 3 hours. After distilling off the solvent, the residue was dissolved in methylene chloride, and the solution was washed with water and evaporated in vacuo. The residue was dissolved in ethanol, and the solution was adjusted to pH 4 with hydrochloric acid. The resulting hydrochloride was recrystallized from isopropanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH3:32])[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH2:31]([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1)[CH3:32]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CCOc1ccccc1CN1CCN(CCCCl)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCOc1ccccc1CN1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 64.3 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-ethoxybenzyl)-piperazine; yield 64.3% of theory; m.p. of the dihydrochloride (recrystallized from ethanol) 223°C;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CON(C)C(=O)c1cc(C)ccc1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 54.7 %

Procedure:
Step AI (1): To a solution of 2-bromo-5-methylbenzoic acid (1000.0 mg, 4.65 mmol) in DMF (100 mL) were added N,O-dimethylhydroxylamine hydrochloride (454 mg, 4.65 mmol), EDC (891 mg, 4.65 mmol), and HOBT (628 mg, 4.65 mmol). The reaction mixture was stirred at rt for 2.5 days. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 2-bromo-N-methoxy-N,5-dimethylbenzamide (656 mg, 55%) as a colorless oil. LC-MS (M+H)+=258.21.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:13][NH2:14]>>[CH3:13][NH:14][C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=1)=[O:11]
Reactant: CN
Reactant: COC(=O)c1nc(Br)cnc1N
Product: CNC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Methyl 3-amino-6-bromo-2-pyrazine-carboxylate (14.3 g, 61.6 mmol; see Example 16 (a) above) was suspended in 40% aqueous methylamine (350 mL) and the resulting mixture was stirred vigorously for 7 hours at room temperature. The precipitate was collected, washed with water, and dried to afford 3-amino-6-bromo-pyrazine-2-carboxylic acid methylamide as a yellow solid (12.7 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ2.77 (d, J=3 Hz, 3H), 7.70 (br s, 2H), 8.33 (s, 1H), 8.56 (q, J=3 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) δ27.84, 123.49, 127.69, 150.43, 156.04, 167.18.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][NH2:27])[CH2:23][O:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][O:22]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC3COC(C)(C)O3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). 2,2-Dimethyl-1,3-dioxolane-4-methanamine (216 mg; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is dissolved in DCM (3 ml). Title compound precipitates with addition diethyl ether, affording after filtration, Compound (14) as a white powder (65 mg; 46%).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)[CH3:14].[CH2:26]([O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])[CH3:27]>C(O)C>[CH2:26]([O:28][C:29]([C:30]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:25])=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:33][C:31]=1[CH3:32])=[O:34])[CH3:27]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc3ccccc23)C(C(=O)OCC)=C(C)N1

Procedure:
After heating a solution of 15.6 g of 1-naphthaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol under reflux for 6-8 hours, and cooling, light yellow crystals of melting point 112° (ethanol) are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[NH3:8].[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1CCOC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Product: N
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-morpholin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (65 mg, 0.12 mmol) in DMF (2 mL) was cooled to −40° C. and treated with methyl iodide (20.5 mg, 0.145 mmol) as a solution in DMF (1 mL) and potassium carbonate (33 mg, 0.24 mmol). The reaction was allowed to warm slowly to rt over 1 h. The reaction was diluted with EtOAc and washed 3 times with water. The organic layer was dried with sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with CH2Cl2:MeOH:NH3 to provide 17.9 mg (34%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.89 (s, 1 H), 7.79 (d, 1 H, J=9 Hz), 7.65 to 7.73 (m, 1H), 7.59 (s, 1H), 7.26 to 7.41 (m, 5H), 7.13 (d, 1 H, J=9 Hz), 6.76 (s, 1H), 5.65 (s, 2H), 4.98 (dd, 1H, J=11, 2 Hz), 4.08 (dd, 1H, J=6, 2 Hz), 3.85 to 3.94 (m, 1H), 3.15 to 3.23 (m, 1H), 2.98 to 3.08 (m, 1H), 2.80-2.96 (m, 2H), 2.11 (s, 3H); ES-MS m/z 440.4 [M+H]+, HPLC RT (min) 2.07.
Reaction SMILES: FC1C=CC(CN2C3C=CC=CC=3N=C2)=CC=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([C:39](OC)=[O:40])[CH2:35][CH2:34]2)=[CH:27][CH:26]=1>C1COCC1.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([CH:39]=[O:40])[CH2:35][CH2:34]2)=[CH:27][CH:26]=1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Agent: Fc1ccc(Cn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(CCN2CCC(C=O)CC2)cc1
Reaction time: 0.29 h

Procedure:
To a stirred, -78° C., solution of 1-[(4-fluorophenyl)methyl]-1H-benzimidazole (1.13 g, 5.00×10-3 mole) and dry THF (12 ml) under argon was added a 2.5 molar hexane solution of n-butyl lithium (2.1 ml, 5.25×10-3 mole). After 15-20 minutes at -78° C., a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (1.39 g, 5.01×10-3 mole) and dry THF (6 ml) was added dropwise via syringe. After 5-10 minutes, the cooling bath was removed and the reaction was allowed to warm. After ca. 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was transferred to a separatory funnel where the aqueous mixture was extracted two times with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a viscous oil. This was purified by a combination of flash chromatography (ethyl acetate) and crystallization (cyclohexane) affording 1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl][1-[2-(4methoxyphenyl)ethyl]-4-piperidinyl]methanone as off white matted needles: 0.90 g (38%), m.p. 109-111° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@@H:35]([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C[C@H](N)CO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (S)-(+)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2 [(M+H)+] 543.2196, observed 543.2200.