Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[S:11].[H-].[Na+].C(N=[N+]=[N-])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl>C1COCC1>[C:15]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[S:11])(=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Reactant: CN1C(=S)Cc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=S)C(C(=O)c2ccccc2)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-2-indolinethione (0.50 g, 3.06 mmol) in dry THF (3 mL) was added dropwise at 20° C. under N2 to a stirred suspension of NaH (0.13 g of a 60% w/w suspension in mineral oil, 3.37 mmol) in THF (2 mL). After gas evolution had ceased (5 minutes), a solution of the above phenacyl azide in THF (2 mL) was added dropwise, and the mixture was stirred at 20° C. for 1 hour, then poured into 6N HCl and extracted with EtOAc. The residue from the organic layer was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (3:7) gave foreruns, and elution with CH2Cl2 /petroleum ether (2:3) gave 3-benzoyl-1-methyl-2-indolinethione [XV: R1 =H, R3 =Me, R5 =C6H5] (24) (0.31 g, 38%); mp (trituration from MeOH) 132°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19]C1C=CC(B(O)O)=C(F)C=1>>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[C:2]([F:1])[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2ccc(Cl)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (4-chloro-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:26]([CH:5]1[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2](=[O:1])[CH2:7][C:6]1=[O:8])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Cc2ccccc2)C(=O)CC1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (Ark Pharm, Inc., Libertyville, Ill.; 2.0 g, 9.389 mmol) in THF (1 L) at 20° C. was added LHMDS (1.0M in THF; 23.47 mL, 23.47 mmol) (dropwise), and the resulting mixture was stirred at 20° C. for 30 min. Benzyl bromide (3.1 g, 18.77 mmol) was added, and the resulting mixture was stirred at 20° C. for 1 h. The mixture was neutralized with 10M aq. KHSO4 solution and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude rac-tert-butyl 5-benzyl-2,4-dioxopiperidine-1-carboxylate (1.0 g) (used without further purification in subsequent transformations): m/z (ESI, +ve) 204.0 [(M+H)-100]+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C@H:15]4[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:17][CH2:16]4)=[N:11][C:10]=3[C:4]=2[CH:3]=1>CCOC(C)=O.Cl.O1CCOCC1>[NH2:22][CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:12]2[S:13][C:9]3[CH2:8][CH2:7][CH2:6][C:5]4[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=4[C:10]=3[N:11]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1

Procedure:
A solution of trans-tert-butyl N-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}-methyl)carbamate (34.5 g, 77.0 mmol) in 200 ml EtOAc and 100 ml 4N HCl in dioxane was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and the solid product washed with Et2O and dried under vacuum to yield 25.9 g of the desired product as a pale yellow solid. An additional 1.43 g of the product was obtained by allowing the filtrate to stand in a closed flask for several days. The overall yield was 85%: 1H-NMR (CD3OD) δ 1.25 (2H, m), 1.51 (2H, m), 1.70 (1H, broad), 1.95 (2H, m), 2.18 (4H, m), 2.80 (6H, m), 3.63 (1H, broad), 7.11 (1H, dt, J=2.5 Hz, 8.4 Hz), 7.36 (2H, m); 346 (ESMS, MH+).
Reaction SMILES: [O-2:1].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].Cl.[Ti:9](Cl)(Cl)(Cl)Cl.[OH-].[NH4+].[Ti].[V]>O>[O-2:1].[V+5:6].[O-2:1].[O-2:1].[O-2:1].[O-2:1].[V+5:6].[O-2:1].[Ti+4:9].[O-2:1]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti]
Agent: [V+5]
Agent: [V]
Solvent: O
Product: [Ti+4]
Reaction time: 16 h

Procedure:
133 g. of vanadium pentoxide was added to a solution prepared from 635 ml of concentrated hydrochloric acid and 340 ml of water and stirred until a homogeneous solution formed. To this solution, 277 g. of titanium tetrachloride was added slowly over a 2 hour period while maintaining the temperature below 40° C. in an inert nitrogen environment. This vanadium-titaninium solution was then added concurrently with 700 ml of an 8 percent solution of ammonium hydroxide solution to 450 ml of water which was cooled in an ice/water bath. The pH of the resulting solution was maintained at 1.4 to 2.0 during the addition of the vanadium-titanium total solution. The pH of the solution was then adjusted to a pH of 5.7, the mixture filtered and the solids thoroughly washed with water and dried at 80° C. in a vacuum oven. The solid was calcined in air at 400° C. for 16 hours to give a vanadium oxide/titanium oxide material. 15.0 g. of the vanadium-titanium solid material was added to 30 ml of a 1N ammonium hydroxide solution which contained 0.625 g. of palladium chloride in solution. This mixture was allowed to stand for 1 hour and then dried at 90° C. in a vacuum oven. The resulting solid was calcined at 400° C. in air for 16 hours to yield a Pd-V2O5 -TiO2 solid catalyst containing as the metal 2.5 percent Pd, 27 percent V and 26 percent Ti.
Reaction SMILES: ClCCl.C([SiH]([CH2:9][CH3:10])CC)C.C(=O)([O-])O.[Na+].[C:16](#N)[CH3:17]>>[CH2:17]([C@H:16]1[CH2:10][CH2:10][C@H:9]([CH:17]2[CH2:16][CH:17]([CH2:9][CH2:16][CH2:17][CH2:9][CH3:10])[CH:16]=[CH:10][CH2:9]2)[CH2:17][CH2:16]1)[CH2:9][CH3:10]
Reactant: CC#N
Reactant: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC1C=CCC([C@H]2CC[C@H](CCC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 6.56 g of compound (r-12) was dissolved into a mixed solvent of 100 mL of dichloromethane and 100 mL of acetonitrile, 3.91 g of triethylsilane was added thereto, and then 4.13 g of trifluoroborane-diethyl ether complex was added dropwise at −50° C., the resultant mixture was stirred at −78° C. for 30 minutes, and then stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added dropwise to terminate a reaction, the resultant mixture was subjected to extraction with dichloromethane, and then organic layers were combined, the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane), and further purified by recrystallization from ethyl acetate, and dried, and thus 1.11 g of 3-(4-(trans-4-propylcyclohexyl)-6-pentylcyclohexene (compound (1-1-1-3)) was obtained.
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])([OH:3])=[O:2]>C(O)C=C>[CH2:8]([O:22][C:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:1]([O:3][CH2:11][CH:10]=[CH2:9])=[O:2])=[O:24])=[O:23])[CH:4]=[CH2:1]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Solvent: C=CCO
Product: C=CCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCC=C
Temperature: 25 °C
Reaction time: 90 h
Yield: 98.3 %

Procedure:
A mixture of 1.02 g (3 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid and 3 g Amberlite® IR120 in 30 ml allylalcohol were stirred at room temperature for 90 hours. After filtration the solvent was distilled off, the residue was taken up in dichloromethane and extracted with 2% aqueous sodium bicarbonate. The organic extract was dried with sodium sulfate and the solvent was distilled off to yield 620 mg (49%) (R)-1-{6-[(R)-2-alloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid allyl ester as alight yellow oil, MS m/e (%): 421 (M+H+, 100).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[F:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.[NH2:47][C:48]([CH3:68])([CH3:67])[C:49]([N:51]1[CH2:56][CH2:55][N:54](C(OCC2C=CC=CC=2)=O)[CH2:53][CH2:52]1)=[O:50].C(N1CCNCC1)C1C=CC=CC=1>>[F:43][C:32]1[CH:33]=[C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49]([N:51]2[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]2)=[O:50])([CH3:68])[CH3:67])[CH:35]=[CH:36][C:31]=1[CH2:30][C:29]1[C:25]([O:24][C@@H:6]2[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]2[OH:4])=[N:26][NH:27][C:28]=1[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1F

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-fluorophenyl}methyl)-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([Si:30]([CH3:32])([CH3:31])[O:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:8]2[CH:19]=[CH:20][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(CN2CCN(CCO)CC2)cc1
Agent: Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 94 %

Procedure:
A suspension of 2-[4-(4-nitro-benzyl)-piperazin-1-yl]-ethanol hydrobromide (as prepared in the previous step, 1.00 g, 2.89 mmol) in DMF (3 mL) was treated with imidazole (688 mg, 10.1 mmol) and tert-butyl-chloro-dimethyl-silane (566 mg, 3.76 mmol) at RT for 3 h. The mixture was partitioned between EtOAc (50 mL) and brine (50 mL), and the layers were separated. The organic layer was washed with brine (3×40 mL). The combined aqueous layers were extracted with EtOAc (1×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 50% EtOAc-hexane afforded the title compound (1.03 g, 94%) as a pale yellow oil which solidified upon standing. Mass spectrum (ESI, m/z): Calcd. for C19H33N3O3Si, 380.2 (M+H). found 380.2.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>>[C:9]1([C:7]2[O:8][C:4]3[CH:3]=[C:2]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:15][C:5]=3[N:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCC(=O)N(C)OC
Product: CCC(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 29a from 6-bromo-2-phenyl-benzoxazole and N-methoxy-N-methyl-propionamide.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[N:12]=[C:11](O)[N:10]=1)[CH2:2]2.O=P(Cl)(Cl)[Cl:22]>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]([Cl:22])[N:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)[CH2:2]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(O)n1
Product: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
In a 250 mL round-bottomed flask was placed 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(isopropylamino)pyrimidin-2-ol (29, 124 mg, 0.469 mmol) in POCl3 (20 ml) to give a yellow solution. The mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature, concentrated, diluted with dichloromethane and washed with saturated NaHCO3 followed by 0.2 N NaOH. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound (91 mg, 69%). Aryl chloride 30 could be transformed into aniline 18 as described in scheme 2 for the conversion of 5 into 6. Aniline 18 could be transformed into urea or carbamate compounds as described in scheme 2 (and illustrated in the experimental section for scheme 7).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([CH2:36][C:37]([O:39]CC)=[O:38])=[C:30]([F:42])[CH:29]=1.[OH-].[Na+].Cl>C(Cl)Cl.O.C1COCC1>[F:42][C:30]1[CH:29]=[C:28]([NH:27][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:13])[C:33]([O:34][CH3:35])=[CH:32][C:31]=1[CH2:36][C:37]([OH:39])=[O:38]
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: CCOC(=O)Cc1cc(OC)c(N)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)O)c(F)cc1NC(=O)c1cn(C)c2ccccc12
Temperature: 0 °C
Yield: 70.9 %

Procedure:
1-Methyl-1H-indole-3-carboxylic acid (700 mg, 4.0 mmol) was dissolved in methylene chloride (8 ml). Oxalyl chloride (0.53 ml, 6.1 mmol) was added dropwise to the solution under stirring at 0° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour and distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (6 ml). The resulting solution was added to a solution of triethylamine (0.84 ml, 6.0 mmol) and ethyl 4-amino-2-fluoro-5-methoxyphenylacetate (909 mg, 4.0 mmol) in methylene chloride (3 ml) under stirring at 0° C. The reaction mixture was heated at reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured into ice water, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 9:1 to 7:3, 12 ml/min, φ 50 mm×300 mm, charged by dry silica gel method). The purified ester was added with THF (45 ml) and 0.25M NaOH (18 ml, 4.5 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and 1M HCl was added to the resulting mixture to make it acidic. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 2-fluoro-5-methoxy-4-((1-methyl-1H-3-indolylcarbonyl)amino)phenylacetic acid (1.01 g, 71%) as a colorless solid.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.NC1C=CC([C:38]([NH2:40])=[O:39])=CN=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[N:6]=[CH:5][CH:4]=[CH:9][C:8]=2[C:38]([NH2:40])=[O:39])=[O:31])=[CH:28][CH:27]=1
Reactant: NC(=O)c1ccc(N)nc1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ncccc2C(N)=O)cc1

Procedure:
The product from Example 1, Part C (160 mg, 0.5 mmol) and 6-aminonicotinamide (103 mg, 0.75 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the aqueous phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (10 mg, 5%). 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2 Hz, 1H), 8.71 (br s, 1H), 8.22 (d, J=9 Hz, 1H), 8.13 (dd, J=9 Hz, 2 Hz, 1H), 7.20 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 5.05 (d, J=15 Hz, 1H), 4.63 (s, 1H), 4.13 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.94 (s, 2H), 1.95 (s, 3H), 1.83 (s, 3H). MS: m/z (MH+) 441.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH3:25])=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH3:25])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C)c3c2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3ccc(CO)o3)cc12

Procedure:
5-(5-Methoxycarbonyl-2-furyl)-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Example 65) was reacted with lithium aluminium hydride, in tetrahydrofuran, using a procedure similar to that described in Example 63. This gave the title compound. Found: C,70.59; H,6.81; N,8.41. C19H22N2O2.3/16CH2Cl2 requires: C,70.62; H,6.91; N,8.59%.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[P:10]([O:19]C(C)C)([O:15][CH:16]([CH3:18])[CH3:17])[O:11][CH:12]([CH3:14])[CH3:13]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:10](=[O:19])([O:15][CH:16]([CH3:18])[CH3:17])[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1CP(=O)(OC(C)C)OC(C)C

Procedure:
34.5 g (0.19 mol) of 2-methylbenzyl bromide and 39 g (0.19 mol) of triisopropyl phosphite were heated at 150° C. for 2 hours. During this procedure, i-propyl bromide distilled off. The product was distilled through a 30 cm Vigreux column.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: C1CNCCN1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3CCNCC3)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), piperazine (413 mg, 6.60 mmol, 10.00 equiv), and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-piperazin-1-yl-ethanone (26): HPLC retention time, 0.30 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 352.9, found, 353.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2.C(N(C(C)C)CC)(C)C>CS(C)=O.[Cl-].[Na+].O>[CH:16]12[N:19]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[F:1])[CH:12]([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2C3CCCC2CC3)c(F)c1
Temperature: 120 °C

Procedure:
3,4-Difluorobenzonitrile (1.75 g; 25.1 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (2.1 g; 13.8 mmol), and diisopropylethylamine (3.2 g; 25.1 mmol), were combined in DMSO (30 mL) and heated at 120° C. overnight. The mixture was allowed to cool to ambient temperature, poured into brine (75 mL), and extracted with diethyl ether (2×50 mL). The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel (ethyl acetate as eluent) to provide the title compound. 1H NMR (DMSO-d6) δ 7.69 (dd, 1H), 7.42 (dd, 1H), 7.15 (t, 1H), 4.41 (s, 2H), 1.98 (m, 2H), 1.62-1.86 (m, 5H), 1.41 (m, 3H); MS (ESI) m/z 231, (M+H)+.
Reaction SMILES: [OH2:1].[PH2]([O-])=O.C([NH+](CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]#N)[CH:16]=[CH:15][C:14]=1[N:21]1[C:25]2[C:26]3[S:30][C:29]([NH:31][C:32](=[O:34])[CH3:33])=[N:28][C:27]=3[CH2:35][CH2:36][C:24]=2[C:23]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[N:22]1>[Ni].ClCCl.CO>[Cl:12][C:13]1[CH:18]=[C:17]([CH:19]=[O:1])[CH:16]=[CH:15][C:14]=1[N:21]1[C:25]2[C:26]3[S:30][C:29]([NH:31][C:32](=[O:34])[CH3:33])=[N:28][C:27]=3[CH2:35][CH2:36][C:24]=2[C:23]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[N:22]1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(c(-c3cccnc3)nn1-c1ccc(C#N)cc1Cl)CC2
Reactant: O
Agent: [Ni]
Agent: CC[NH+](CC)CC
Agent: O=[PH2][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1c(c(-c3cccnc3)nn1-c1ccc(C=O)cc1Cl)CC2
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a hydrogenation reactor under an argon atmosphere, triethylammonium hypophosphite hydrate (2.2 mL, 12 mmol) is added at 10° C. to a suspension of Raney nickel (8 g, 93 mmol) in 75 mL dichloromethane and 75 mL methanol. After the release of gas has died away N-[1-(2-chloro-4-cyanophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide (PCT/EP05055021) (2.7 g, 5.6 mmol) is added and the mixture is stirred for 3 h at 55° C. The reaction mixture is filtered and the filtrate is evaporated down. The residue is purified on silica gel with dichloromethane/methanol.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[O:12]=[S:10]1(=[O:11])[C:3]2[C:2](=[CH:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=2)[C:15]2[C:14](=[C:23]3[C:18](=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[N:22]3)[NH:13]1
Reactant: N#Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 4.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-cyano-N-quinolin-8-yl-benzenesulfonamide (Intermediate 278) (350 mg, 1.08 mmol), t-butyl nitrite (0.19 ml, 1.62 mmol), AcOH (3.5 ml) and THF (3.5 ml) gave the title compound (15 mg, 4%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.