Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1([C:23]#N)[CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1([CH:23]=[O:28])[CH2:22][CH2:21][CH2:20]1
Reactant: N#CC1(c2ccccc2C(F)(F)F)CCC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.7 ml of diisobutylaluminum hydride was added dropwise over 2 hours to a solution of 8.5 g of 1-(2-trifluoromethyl-phenyl)-cyclobutanecarbonitrile in 85 ml toluene at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of 5% sulfuric acid in ice-water, and stirred for 10 minutes. The mixture was extracted four times with ether. The combined ether extracts were dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 5%) to yield 6.2 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[N:9]([CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:8]2=[O:23].Cl.Cl[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[N:9]([CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:21][CH2:22]1)[C:8]2=[O:23]
Reactant: COc1cccc2c(=O)n(CCCC3CCNCC3)c(C)nc12
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(C)nc12
Temperature: 25 °C

Procedure:
A mixture of the product from Step B (331 mg, 0.94 mmol), N-(3-chloropropyl)piperidine hydrochloride (666 mg, 1.88 mmol), potassium carbonate (260 mg, 1.88 mmol) and potassium iodide (312 mg, 1.88 mmol) in THF/H2O (3:1 mixture, 40 mL) was heated under reflux for 17 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with sat'd aq NaHCO3, sat'd aq brine, dried and concentrated. The crude residue was chromatographed on SiO2-gel using a solvent gradient of 100% EtOAc to EtOAc/NEt3 (10:1) to give the product as a yellow oil. API-MS: 441 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.3 (t, 1 H), 7.1 (d, 1 H), 4.03 (t, 2 H), 4.9 (s, 3 H), 3.9 (m), 2.7 (s, 3 H), 2.3 (m), 1.8-1.2 (m).
Reaction SMILES: [Na].[C:2]1([CH2:8][C:9]([O:11]CC)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=[O:16].Cl>O>[C:2]1([CH2:8][C:9](=[O:11])[CH2:14][C:15](=[O:16])[CH3:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(=O)CC(=O)Cc1ccccc1
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Sodium (28 g) was added in small portions to a solution of ethyl phenylacetate (600 g, 3.66 moles) and acetone (70.7 g, 1.22 moles) under nitrogen, was dissolved at 30°-40° C. with stirring for 1 hour and then the mixture was reacted at 70°-80° C. for 4.5 hours. The reaction mixture was taken up in H2O (1.2 l), neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residue was distilled under reduced pressure to give 53.2 g of the desired product as a colorless oil having a boiling point of 142°-146° C./15 mmHg. [Lit.: bp. 133°-136° C./10 mmHg; K. G. Hampton, T. M. Harris, C. R. Hauser, Org. Synth., 51., 128 (1971).]
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([CH2:23][O:24][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:20]([O:25][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Sodium hydride (140 mg, 60% oil dispersion, 3.7 mmol) was added portionwise to a stirred solution of benzyl bromide (300 μL, 2.8 mmol) and 1 (200 mg, 0.92 mmol) in DMF (10 mL) at 0° C. On complete addition the resulting suspension was allowed to warm to r.t., diluted with toluene (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to afford a syrup. Chromatography afforded 2 (350 mg, 96%) as an oil which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:17][CH3:16])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccccc2Cl)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccccc2Cl)C1
Reaction time: 16 h

Procedure:
A stirred solution of 4.5 g (0.018 mol) of 3-(2-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 h. The reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (4.3 g). The crude product was recrystallized from benzene/ligroin yielding 3.9 g (90.0%) of fine white crystals, mp 129.5°-131.5° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[N:31][C:30]=23)=[O:25])[CH2:11][CH2:10]1)=O)(C)(C)C>ClCCl>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[C:17]([NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[N:31][C:30]=23)=[O:25])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2NC(=O)c2cnn3cccnc23)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1OC1CCNCC1)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 144.4 %

Procedure:
A solution of hydrochloric acid (1 M in E2O, 10 mL) was added, at room temperature, to a solution of 4-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.424 mmol) in dichloromethane (5 mL) and the resulting mixture was stirred at room temperature for 60 hours. The solid formed was collected by filtration and washed once with dichloromethane, 3 times with methanol, once again with dichloromethane and once with hexane, then was dried in a vacuum oven at 60° C. to afford 125 mg (72% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-(piperidin-4-yloxy)-phenyl]-amide hydrochloride salt as an off-white solid. MS=372 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH3:29][C:30]1([CH3:35])[CH2:34][CH2:33][N:32]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:31]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC1(C)CCNC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(C)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3,3-dimethylpyrrolidine via General Procedure E to give 16.8 mg of 300 following reverse phase purification. MS (Q1) 461.2 (M)+
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([NH2:25])=[C:20]([NH2:26])[CH:19]=1>>[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]2[N:25]=[C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)[NH:26][C:20]=2[CH:19]=1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Cc1cc(N)c(N)cc1C
Product: Cc1cc2nc(-c3ccc(C=C4SC(=O)NC4=O)cc3)[nH]c2cc1C

Procedure:
5,6-Dimethyl-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 4,5-dimethyl-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.O1CCCC1>[CH:14]1([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (0.72 g, 0.0039 mol) and cyclobutanone (0.87 mL, 0.012 mol) in acetonitrile (10 mL) and tetrahydrofuran (10 mL) was added sodium triacetoxyborohydride (2.4 g, 0.012 mol). The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with aq. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl 4-cyclobutylpiperazine-1-carboxylate, which was treated with 4.57 M hydrogen chloride in 1,4-dioxane (10 mL, 0.04 mol) at room temperature for 2 hours and then evaporated to dryness to give the desired product. LCMS calculated for C8H17N2 (M+H)+: m/z=141.1; Found: 141.2
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2S[CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:49]([O-:52])([O-])=[O:50].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[S:49](=[O:52])(=[O:50])[CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1
Reactant: COc1cc2c(cc1OC)SCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)S(=O)(=O)CCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Reaction time: 15 h

Procedure:
In methylene chloride (10 ml) is dissolved 1-(7,8-dimethoxy-2,3-dihydro-1-benzothiepin-4-carbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.6 g) obtained in Working Example 24. To the solution is added, while stirring under ice-cooling, m-chloro-perbenzoic acid (1.71 g) in limited amounts. The mixture is stirred for one hour, and then left standing at -5° C. for 15 hours. To the reaction mixture is added an aqueous solution of acid sodium sulfite to decompose the excess peracid. The resultant is poured into an aqueous solution of sodium hydrogencarbonate; this is followed by extraction with methylene chloride. The organic layer is washed with an aqueous solution of sodium hydrogencarbonate, dried, and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 1-(7,8-dimethoxy-1,1-dioxo-2,3-dihydro-1-benzothiepin4-carbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine as colorless prisms (1.4 g), m.p. 226°-229° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>C(OCC)C.O1CCCC1.CO>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH:19]([NH2:20])[C:18]2[CH:21]=[CH:22][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:16][CH:17]=2)=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Mg]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
A suspension of 5 mmol magnesium-turnings in 10 ml diethyl ether was treated with 5 mmol 4-bromobenzotrifluoride to form the corresponding Grignard-reagent. This reagent was slowly added to a cooled solution of 5 mmol 4-(trifluoromethyl)benzonitrile in 10 ml of tetrahydrofuran at −70° C. After 1 hour at −70° C., the reaction mixture was stirred additional 2 hours at room temperature and then refluxed overnight. The resulting mixture was cooled again to 0° C. and diluted with 10 ml of methanol and 10 mmol sodium borohydride were added. After stirring for 2 hours at room temperature, the mixture was poured into 100 ml of 0.5 M aqueous hydrochloric acid and extracted with diethyl ether. The aqueous phase was adjusted to pH=10 by addition of diluted aqueous sodium hydroxide and extracted 3 times with dichloromethane. Chromatography (SiO2; dichloromethane/methanol) yielded the title compound as a slightly brown foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30]([NH:33][C:34](=[O:38])[CH:35](Br)[CH3:36])(=[O:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30]([NH:33][C:34](=[O:38])[CH:35]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[CH3:36])(=[O:31])=[O:32]
Reactant: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Br)c1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)c1
Temperature: 45 °C
Yield: 83.7 %

Procedure:
To a stirred solution of 0.75 g (0.0026 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.89 g (0.0026 mole) of N-(2,5-dimethoxyphenylsulfonyl)-2-bromopropionamide in 50 mL of acetone was added 1.04 g (0.0026 mole) of potassium carbonate. After complete addition the mixture was heated at 45° C. for two days. The resultant mixture was cooled and the solvent was removed by evaporation under reduced pressure to leave a residue. The residue was dissolved in 100 mL of water. The aqueous solution was acidified by the dropwise addition of concentrated hydrochloric acid producing a precipitate. The precipitate was collected by filtration. The filter cake was washed with water and then dried under reduced pressure to leave 1.23 g of N-(2,5-dimethoxyphenylsulfonyl)-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide (mp 168°-172° C.) Compound C90.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccnc1
Yield: 14 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with pyridine-3-boronic acid (available from Combi-Blocks Inc.; 49 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-pyridin-3-yl-benzoic acid (12 mg, 14%). 1H NMR (300 MHz, DMSO-d6), δ 13.27 (br s, 1H), 8.56-8.63 (m, 2H), 8.45-8.51 (m, 2H), 8.34 (d, J=1.9 Hz, 1H), 8.28 (dd, J=7.9, 1.9 Hz, 1H), 8.10 (dd, J=8.5, 2.1 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.48 (dd, J=7.7, 5.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:22]([F:24])[F:23])[N:6]2[CH:13]([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:22]([F:23])[F:24])[N:6]2[CH:13]([CH3:21])[C:14]([OH:16])=[O:15]
Reactant: CC(C(=O)OC(C)(C)C)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]propanoate (0.072 g, 0.2 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL) and stirred at rt for 4 h. The mixture was concentrated in vacuo. The residue was diluted with Et2O and hexane was added while stirring. The solids were collected by filtration and washed with hexane to afford the title compound as a white solid (0.058 g, 95% yield): MS (ES) m/z 299 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[NH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])N>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:8]([CH3:15])([CH3:14])[C:7]3[NH:17][C:19]4[C:26]([C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4
Reactant: COc1cc2c(cc1Cl)CCC(=O)C2(C)C
Reactant: N#Cc1cccc(NN)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Cl)Cc1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound I1-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g, 1.2 eq.) were dissolved in TFA (91 mL), and stirred at 90° C. for 3 hr. According to the concentration under reduced pressure, TFA was removed and the residues were added with saturated aqueous solution of NaHCO3, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with 11-3 (red powder, 6.46 g).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=2)=[O:29])[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:3]([N:24]1[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][C:16]([NH:27][C:28]([C:30]3[NH:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=3)=[O:29])=[C:15]([N:12]3[CH2:13][CH2:14][CH:9]([CH3:8])[CH2:10][CH2:11]3)[CH:20]=2)[CH2:26][CH2:25]1)(=[O:4])[CH3:2]
Reactant: CC1CCN(c2cc(N3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.5 %

Procedure:
To 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide trifluoroacetic acid salt (as prepared in Example 56, step (b)) (30 mg, 0.048 mmol) in dichloromethane (5 mL) was added acetic anhydride (7.0 μL, 0.072 mmol) and DIEA (31 μL, 0.18 mmol) and the mixture was stirred for 5 h at RT. The mixture was poured into saturated aq sodium bicarbonate (5 mL), extracted with dichloromethane (5 mL), and the organic layer was dried (Na2SO4). The solvents were removed in vacuo and the resulting residue was purified by silica gel preparative TLC eluting with 10% methanol in dichloromethane to yield 4.9 mg (23%) of the title compound as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 10.57 (br s, 1H), 8.99 (s, 1H), 8.27 (d, 1H, J=8.8 Hz), 7.45 (dd, 1H, J=3.1, 1.3 Hz), 6.851 (s, 1H), 6.81 (d, 1H, J=3.5 Hz), 6.73 (dd, 1H, J=8.9, 2.6 Hz), 3.79 (m, 2H), 3.64 (m, 2H), 3.17-2.96 (m, 4H), 2.74 (m, 2H), 2.70 (m, 2H), 2.15 (s, 3H), 1.87-1.84 (m, 2H), 1.58 (m, 1H), 1.44-1.34 (m, 2H), 1.08 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C24H31N6O2, 435.2 (M+H); found: 435.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21]>C1COCC1.C(OC)(C)(C)C.[Pd]>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[NH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CN=[N+]=[N-]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccccc1CN
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 78.0 g (0.312 mol) 2-azidomethylphenylacetic acid t-butyl ester in 1.36 L THF was added 7.8 g (50% water wet) 5% Pd on C and the mixture shaken mechanically in a 2 L heavy-walled flask under H2 at 45 psi for 2 h. The catalyst was removed by filtration through a bed of celite, rinsing with 250 mL THF. To the filtrate was added a solution of 31.25 g (0.347 mol) oxalic acid in 500 mL methyl tert-butyl ether, and the resultant suspension stirred at room temperature for 30 min. The solid was collected on a filter and washed with 300 mL methyl tert-butyl ether (the filtration was very slow, requiring about 3 hours). Drying under reduced pressure at 60° C. for 18 h gave 42.4 g (39% overall from 2-bromomethylphenylacetic acid) tert-butyl [2-(aminomethyl)phenyl]acetate oxalate salt as a white powder. The product is unstable as the free base, and will cyclize to the amide over several hours at room temperature.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2](=[O:3])[O:4][CH2:5][CH3:6])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: CCOC(=O)Cl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC
Yield: 81.3 %

Procedure:
Using the general method of Example 55, ethyl chloroformate (46 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.15 g of ethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C20H28N6O2: % C, 62.48; % H, 7.34; % N, 21.86; Found: % C, 61.73; % H, 7.28; % N, 21.62.