Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:8]1)=[O:6])[CH3:3].[C:25](OC(=O)C)(=[O:27])[CH3:26].[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:1].[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([O:13][C:25](=[O:27])[CH3:26])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 g (5.6 mmol) of cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride and 20 ml of acetic anhydride are heated under reflux in 100 ml of toluene for 18 hours. 200 ml of ice-water are then added to the cooled reaction mixture and the whole is stirred for 30 minutes. The reaction mixture is rendered alkaline to pH 10 with 2N sodium hydroxide solution and the toluene phase is then separated off. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated by evaporation. The crude product so obtained is purified by chromatography over the 10-fold amount of silica gel with diethyl ether as eluant. The purified product is converted into the hydrochloride and crystallised from ethanol/diethyl ether. Cis-4-acetoxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. 202°-203° is obtained.
Reaction SMILES: C1(S([O:10][C:11]2[CH:12]=[N:13][C:14]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:21][S:18]([CH2:17][C:14]1[N:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cc1ccc(OS(=O)(=O)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(O)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-[(methylsulfonyl)methyl]pyridin-3-yl benzenesulfonate (30 g) in ethanol (200 mL) and tetrahydrofuran (200 mL) was added 1N aqueous sodium hydroxide solution (190 mL), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, 1N hydrochloric acid (190 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (13.9 g, yield 79%) as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:41][CH2:40]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.33 mmol) was dissolved in tetrahydrofuran (20 ml), pyridine (360 ml, 4.66 mmol) was added thereto, and the mixture was stirred for 30 minutes. N-methylhomopiperazine (434 μl, 3.49 mmol) was added thereto, and the mixture was refluxed for 12 hours and filtered. The filtrate was concentrated, subjected to column chromatography (eluent: chloroform:methanol=3:1(v/v)), concentrated again, and then crystallized from dimethylether to give 4-(4-methylhomopiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (0.71 g).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]([F:57])([F:56])[CH:49]1[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]1>>[Cl:17][C:18]1[C:19]([O:55][C@H:52]2[CH2:53][CH2:54][C@H:49]([C:48]([F:47])([F:56])[F:57])[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(O[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 4-(trifluoromethyl)cyclohexanol, the title compound was obtained as a colorless solid (0.02 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.40 (d, J=12.6 Hz, 1H), 4.61-4.53 (m, 1H), 2.87 (s, 6H), 2.45-2.32 (m, 1H), 2.18-2.10 (m, 2H), 1.97-1.89 (m, 2H), 1.55-1.44 (m, 4H); MS (ES−) m/z 445.1, 447.1 (M−1).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[N+:19]([C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1N)([O-:21])=[O:20]>[Cu](F)F.N1C=CC=CC=1>[N+:19]([C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])([O-:21])=[O:20]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 66.5 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 7.84 g (76 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) fluoride, 120 mL of pyridine and 8.6 g (50 mmol) of 2-nitro-4-chloroaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 5.2 g of the title compound as a light yellow oil in 66.7% yield. The structure is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:31]([CH:34]2[CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH2:4]1)[CH3:2].O1CCOCC1.[OH-].[Na+].CCOC(C)=O>O.CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:31]([CH:34]2[CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A mixture of N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (8.00 g, 13.8 mmol), 1,4-dioxane (80 mL) and 1 N aqueous NaOH (30.0 mL, 30.0 mmol) was heated at about 60° C. for about 2 h. Then the reaction was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography eluting with a gradient of 0-100% DCM/MeOH/Et2NH (970:27:3) in DCM followed by DCM/MeOH/Et2NH (950:45:5). The product-containing fractions were combined, concentrated under reduced pressure, and dried in a vacuum oven at about 70° C. for about 12 h to give a solid. The solid was triturated with Et2O, filtered while washing with additional Et2O, and dissolved in hot MeOH. The solution was concentrated under reduced pressure to give a solid. The solid was dissolved in hot MeOH (˜200 mL), sonicated while cooling until a suspension formed, concentrated under reduced pressure, and dried in a vacuum oven at about 50° C. to give an off-white solid. To the solid was added EtOAc (30 mL) to give a suspension which was heated briefly with a heat gun and then sonicated for about 15 min. After sitting at ambient temperature for about 15 min, the resulting white solid was collected by vacuum filtration, washing with additional EtOAc (15 mL), and dried in a vacuum oven at about 50° C. The solid was dissolved in hot EtOH (˜200 mL), filtered to remove minor insolubles (<10 mg), sonicated for about 10 min, while cooling, to give a white suspension, which was concentrated under reduced pressure. The resulting white solid was dried in a vacuum oven at about 60° C. to give N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (3.43 g, 67%): LC/MS (Table 2, Method a) Rt=1.67 min; MS m/z: 375 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].CS(C)=O>O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Clc1ccc2ccccc2n1
Reactant: NCCCCO
Solvent: CS(C)=O
Solvent: O
Product: OCCCCNc1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
2-Chloroquinoline (3.26 g, 20 mmol) and 4-amino-1-butanol are dissolved in anhyd. DMSO (10 mL) and heated to 140° C. for 4 hrs. The reaction is cooled to r.t., poured into water (250 mL) and extracted with ethyl acetate (3×100 mL). The organic fractions are pooled and washed with brine (3×150 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material is purified by flash chromatography (silica, 7% methanol in dichloromethane) to give the title compound. MS (ESI) 217 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=Cc1ccccn1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2NCc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a solution of 0.090 g (0.35 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one in 3.5 ml of dichloromethane was added 0.030 mL (0.36 mmol) of 2-pyridine carboxaldehyde, 0.184 g (0.87 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. A recrystallization in isopropanol gives 0.042 g (35%) of pure product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 65 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 65%. Amorphous.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: C([NH:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)[P:16]([OH:18])[OH:17]
Reactant: CC(=O)Nc1ccc(C(NC(c2ccccc2)c2ccccc2)P(O)O)cc1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: CC(=O)Nc1ccc(C(N)P(O)O)cc1

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(4-acetamidophenyl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(4-acetamidophenyl)-methanephosphonous acid. This was treated with dilute hydrobromic acid at reflux followed by propylene oxide to give DL-1-amino-1-(4-aminophenyl)-methanephosphonous acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].O>C(O)(C)C>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([NH:15][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCCN
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: O
Solvent: CC(C)O
Product: CCCNc1nc(N)c(C=O)nc1Cl
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
In 1.2 ml of isopropyl alcohol there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (0.095 g) 0.0005 M) prepared in Step B, after which n-propylamine (32 g; 0.042 ml; 0.00055 M) was added, and the reaction mixture was stirred at room temperature for 20.5 hours. When water was added to the reaction mixture, product precipitated, was filtered, and dried (23 mg). Additional product precipitated, was filtered, and dried (46 mg). The product was recrystallized from ethyl acetate/hexane. Elemental Analysis for C8H11N4OCl.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](Cl)(Cl)=[S:19]>O1CCOCC1.O>[Cl:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([Cl:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reaction time: 8 h

Procedure:
A mixture of N-(3-amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide (0.95 g, 3.4 mmol) in 4.0 mL dioxane is added to thiophosgene (0.45 mL, 5.8 mmol) in 2.5 mL water. The mixture is stirred overnight, extracted with DCM and the organic phase is washed with 5% aq NaHCO3 solution and water and dried with Na2SO4. After fltration and concentration, the crude product is diluted with DCM, filtered through a pad of silica gel and concentrated.
Reaction SMILES: Br[C:2]1[S:11][C:5]2[S:6][C:7](Br)=[C:8]([CH3:9])[C:4]=2[C:3]=1[CH3:12].B([O-])[O-].[CH2:16]([C:22]1[CH:23]=[CH:24][S:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].[Na+].[Na]>COCCOC.C(OCC)C>[CH2:16]([C:22]1[CH:23]=[C:24]([C:2]2[S:11][C:5]3[S:6][C:7]([C:24]4[S:25][CH:26]=[C:22]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:23]=4)=[C:8]([CH3:9])[C:4]=3[C:3]=2[CH3:12])[S:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccsc1
Reactant: Cc1c(Br)sc2sc(Br)c(C)c12
Agent: [Na+]
Agent: [Na]
Agent: [O-]B[O-]
Solvent: CCOCC
Solvent: COCCOC
Product: CCCCCCc1csc(-c2sc3sc(-c4cc(CCCCCC)cs4)c(C)c3c2C)c1

Procedure:
To a solution of 2,5-dibromo-3,4-dimethylthieno[2,3-b]thiophene (3.02 g, 9.28 mmol) and sodium 4-hexylthiophene boronate (5.14 g, 20.4 mmol) in degassed DME (200 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 5 mol %). The solution was heated to reflux and a saturated solution of sodium hyodrogen carbonate (4.2 g, 49 mmol) was added slowly. The reaction was refluxed for 16 h, cooled and diluted with diethyl ether. The layers were separated and the organics washed with 5% HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica (eluent: petrol) to afford the product after recrystallisation from petroi (1.03 g, 22%). :M/Z 500 (M+). Found C, 66.9.1, H, 6.9, S, 25.3. Calc. for C28H36S4 C, 67.2; H 7.2, S, 25.6. NMR gave the expected signals.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=O.BrCC1C=CC=CC=1C#[N:18]>>[NH2:18][O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[C:3]#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: N#Cc1ccccc1CBr
Product: N#Cc1ccccc1CON

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 2-bromomethyl-benzonitrile. 13C-NMR (CDCl3) δ 141.3, 132.9, 132.8, 129.5, 128.4, 117.5, 112.4, 75.3
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[C:28](Cl)=[O:29])([CH3:26])[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[N:27]([CH:31]([CH3:33])[CH3:32])[CH:24]([CH3:26])[CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N(C(C)C)C(C)C)nc3cc21

Procedure:
3-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropyl-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.97 mmol) and diisopropyl carbamyl chloride (158 mg, 0.97 mmol). The title compound was obtained as yellow powder (55 mg, 12%).
Reaction SMILES: Br[C:2]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][C:5]([O:6]C2CCCCO2)=[C:4]([F:23])[CH:3]=1.[Li]CCCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C>C1COCC1>[F:23][C:4]1[C:5]([OH:6])=[CH:13][C:14]2[CH2:15][O:16][B:29]([OH:30])[C:2]=2[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Br)c(COC2CCCCO2)cc1OC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB1OCc2cc(O)c(F)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of 2-(4-bromo-2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (6.31 g, 16.2 mmol) in anhydrous THF (13.5 mL) was made before cooling the reaction mixture in a −78° C. bath. Reaction mixture was then treated, drop-wise, with n-BuLi (12.15 mL, 19.45 mmol) and allowed to stir for 1.0 hr before (i-PrO)3B (5.59 mL, 24.3 mmol) was added via syringe. After the addition of (i-PrO)3B, the reaction mixture was warmed to room temperature and allowed to stir for 2 hr before quenching the reaction with equal volume of concentrated NH4Cl(aq) and EtOAc (1:1, 30 mL). The layers were separated and the water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 6-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol (2.01 g, 73.93%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 4.85 (s, 2H), 6.95 (d, J=5.4 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 8.98 (s, 1H), 10.22 (s, 1H).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH2:27][CH:26]([NH2:28])[CH2:25]1>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:28][CH:26]2[CH2:27][N:24]([CH3:23])[CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CN1CC(N)C1
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CN(C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared similarly to that described in Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.135 mmol), 1-methylazetidin-3-amine (87 mg, 0.405 mmol), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high-throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-((1-methyl-3-azetidinyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (MeOH-d4) δ: 7.80-7.85 (m, 1H), 7.63-7.68 (m, 1H), 7.36-7.42 (m, 1H), 6.93 (s, 1H), 3.59-3.65 (m, 2H), 3.22-3.26 (m, 2H), 3.11-3.14 (m, 1H), 2.97-3.04 (m, 2H), 2.59 (s, 3H), 2.01 (s, 3H). m/z (ESI, +ve) 363.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH:24]=O)[N:9]=2)[CH:7]=1.[CH3:27][NH:28][CH3:29].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][N:28]([CH2:24][C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:26])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:22][CH2:23]1)=[O:20])[N:14]=[CH:15]2)[CH3:29]
Reactant: CNC
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CN(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a slurry of N-(7-(5-fluoro-2-methylphenyl)-5-formyl-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg, 0.08 mmol) in methylene chloride (0.5 mL) was added a 2.0M solution of dimethylamine in tetrahyrdofuran (0.052 mL, 0.1 mmol) and the reaction mixture was stirred at room temperature. After 1 hour, sodium triacetoxyborohydride (27 mg, 0.13 mmol) was added, and the reaction mixture was stirred for another 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% ammonium hydroxide over 14 min) to afford the title compound as a pale yellow solid (22 mg, 70%). 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.28 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.41-7.28 (m, 2H), 7.18 (td, J=8.5, 2.8 Hz, 1H), 3.92 (s, 2H), 2.36 (s, 3H), 2.25 (s, 6H), 2.14-2.07 (m, 1H), 0.87 (m, 4H). LCMS (Method E): RT=3.929 min, M+H+=379.1.