Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][C:6]1[N:10]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:3][C:2]#[CH:1])[C:34]=2[CH2:33][CH2:32]1
Reactant: C#CCBr
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCn1c2c(c3ccccc31)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 60 h

Procedure:
Propargyl bromide (0.086 ml) was added to a suspension of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) and potassium carbonate (265 mg) in acetone (10 ml) and the mixture was stirred under nitrogen for 60 h. More propargyl bromide (0.086 ml) was added and the mixture was stirred at room temperature for 24 h and then at reflux for 6 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a gum (650 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 80:19:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (95 mg) as a foam, t.l.c. on Et3N impregnated SiO2 (ethyl acetate:hexane 4:1) Rf 0.30.
Reaction SMILES: [CH3:1]C(C)=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](O)[CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[CH3:1][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: Oc1ccc2cccc(O)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc2cccc(OC)c2c1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To one liter of acetone were added 50.0 grams (0.31 mole) of 1,7-dihydroxynaphthalene. To the solution then were added 95.0 gm (0.69 mole) of powdered potassium carbonate and 65 mL (0.69 mole) of dimethyl sulfate. The reaction mixture was stirred at reflux under nitrogen for 18 hours. The reaction mixture then was cooled to room temperature and diluted with 2 L of water. The mixture was then extracted with dichloromethane. The organic extracts were combined, washed successively with water and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated in vacuo to give a brown oil. The oil was distilled in vacuo to give 52.51 gm (90.1%) of 1,7-dimethoxynaphthalene as a light orange, transparent oil, b.p.=115°-157° C. (4 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[O:21]=[C:20]1[N:8]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2c(=O)[nH]c3ccccc32)cc1
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-[(2-aminophenyl)amino]benzoate from Step B (442 mg, 1.72 mmol) and 1,1′-carbonyldiimidazole (652 mg, 4.02 mmol) in THF (10 mL) was heated at 75° C. for 3 h. The cooled mixture was partitioned between EtOAc (100 mL) and 10% aqueous citric acid (50 mL). The organic layer was washed with H2O (30 mL), then brine (30 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 75:25, to give the title compound. MS: m/z=283 (M+1).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:12]2[N:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10])([O-])=O.O.NN>CO>[NH2:1][C:4]1[S:5][C:6]([C:12]2[N:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)n1
Agent: NN
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c(N)s2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-nitro-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)thiophene-3-carboxamide (600 mg, 1.62 mmol) in MeOH (25 mL) was added FeCl3 (13 mg, 0.081 mmol). The solution was heated to reflux, and hydrazine hydrate (65%, 0.364 ml, 4.87 mmol) was added. After stirring for 30 minutes at reflux, the mixture was cooled to room temperature, combined with MeOH and silica gel, and evaporated to dryness. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6]C=1C#N.[O:12]1[CH2:17][CH2:16]OCC1.O.S(=O)(=O)(O)[OH:20]>>[F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:16]=1[C:17]([OH:12])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: C1COCCO1
Reactant: Cc1ccc(C#N)c(F)c1I
Solvent: O
Product: Cc1ccc(C(=O)O)c(F)c1I
Temperature: 110 °C

Procedure:
To a solution of 2-fluoro-3-iodo-4-methylbenzonitrile (3.9385 g, 11.316 mmol; 76% mass % pure) in 1,4-dioxane (10.0 mL, 128 mmol) was added water (4.0 mL, 220 mmol) and sulfuric acid (6.0 mL, 110 mmol). The reaction mixture was heated at 110° C. for 20 hours. The reaction mixture was cooled to room temperature and then poured into ˜200 mL ice water. The resulting tan precipitate was collected by filtration, washed with water and ethyl acetate, and dried under vacuum to provide the title product. The filtrate was transferred to a separatory funnel, and the ethyl acetate layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo to yield additional desired product for a combined yield of 3.8743 g which was carried forward without purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1.Cl[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:14][CH2:15]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][CH2:30][C:31]([OH:33])=[O:32])=[O:28]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(O)c2)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCC(=O)O)c2)c1N
Temperature: 100 °C
Yield: 30.4 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (400 mg, 1.06 mmol) and t-butyl chloroacetate (319 mg, 2.12 mmol) in DMF (20 mL) was added K2CO3 (292 mg, 2.12 mmol) and the mixture was heated at 100° C. overnight. The solvent was removed, and the residue was suspended in EtOAc, washed by water, brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc:Hexane=3:1) to provide the product as a light yellow oil (140 mg, 27%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.F[P-](F)(F)(F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:30][O:29][N:20]([CH3:24])[C:10]([C:2]1[NH:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cccnc2[nH]1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (from MolBridge, 1.0 g, 6.2 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 g, 8.0 mmol) and triethylamine (4.3 mL, 31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (0.78 g, 8.0 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-65% EtOAc/hexane) to give the desired product (1.0 g, 79%). LCMS calculated for C10H12N3O2(M+H)+: m/z=206.1. Found: 206.1.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:10])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.[CH:11]1(NC)CCCC1>O1CCOCC1>[CH:1]1([NH:7][C:8](=[S:10])[NH:9][CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC1CCCC1
Reactant: NC(=S)Nc1ccccc1
Solvent: C1COCCO1
Product: CNC(=S)NC1CCCC1

Procedure:
14.5 g of N-[4-(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-phenyl-thiourea were dissolved in 50 ml of dioxane. After addition of 6 g of cyclopentyl-methylamine, the whole was heated for 2 hours to the boiling temperature under reflux. After having removed the dioxane by distillation, the residue was dissolved in 1% aqueous ammonia. The solution was filtered through charcoal and acidified with dilute hydrochloric acid. The N-[4-(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-methyl-thiourea so obtained was found to melt, after recrystallization from methanol, at 152° - 154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]([NH2:9])[CH3:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:9][C@H:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:8])[CH:16]=[N:17][CH:18]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: Clc1cncc(Cl)n1
Product: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Yield: 78.8 %

Procedure:
In a procedure analogous to example 1, reaction of 4-methoxy-α-methyl-benzylamine (700 mg, 4.6 mmol) and 2,6-dichloropyrazine (626 mg, 4.2 mmol) furnished the product (873 mg, 79%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:28])([F:27])[C:21]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][CH2:25][C:21]([OH:26])([C:20]([F:28])([F:27])[F:19])[CH2:22]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: OC1(C(F)(F)F)CCNC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CCC(O)(C(F)(F)F)C1
Yield: 47.3 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 19.7 mg, 103 μmol) to obtain the title compound (15 mg, 47%) as colorless liquid, MS (EI): m/e=371.3 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:11][O:10][C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[F-:18].[K+].CS(C)=O>O>[F:18][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:11][O:10][C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: [F-]
Reactant: CO[C@H](C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CO[C@H](C)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 120 °C
Yield: 87.5 %

Procedure:
To a microwe vial with stir bar was added (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol), potassium fluoride (327 mg, 5.63 mmol) and DMSO (4 mL). Vial capped and heated to 120° C. in a sand bath for 3 hr. Reaction mixture was then cooled to room temperature, diluted with water and aqueous mixture extracted with EtOAc. The Organic phases were combined and washed with water, brine, dried (Na2SO4), filtered and concentrated to afford a white crystalline of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (117 mg, 0.49 mmol, 86% yield). LCMS m/z 242.1 (M+H)+, Rt 0.63 min.
Reaction SMILES: [CH:1]([OH:6])([OH:5])[C:2]#[C:3][CH3:4].[CH2:7]([OH:11])CCC>C(O)CC>[CH2:4]([OH:11])[CH2:3][CH2:2][CH2:1][OH:6].[CH3:7][CH:2]([CH2:3][CH3:4])[CH:1]([OH:6])[OH:5]
Reactant: CCCCO
Reactant: CC#CC(O)O
Solvent: CCCO
Product: CCC(C)C(O)O
Product: OCCCCO

Procedure:
Using a method similar to Example 1, 170 g/h of butynediol solution were hydrogenated over 10 g of Raney Ni/Mo (2.5% by weight of molybdenum, calculated as Mo). The initial temperature was 150° C. and the reactor temperature rose to 173° C. during the reaction. The product was obtained in an amount of 176 g/h and comprised 92.4% by weight of 1,4-butanediol, 0.4% by weight of 2-methylbutanediol, 2% by weight of n-butanol and 4.7% by weight of n-propanol plus a few further products in amounts of less than 0.08% by weight. The STY was 0.7 kg of butanediol/l·h.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)=[O:29])=[CH:25][C:24]([C:44]([CH3:47])([CH3:46])[CH3:45])=[N:23]2)=[CH:18][CH:17]=1>ClCCCl>[C:44]([C:24]1[CH:25]=[C:26]([NH:27][C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)=[O:29])[N:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([NH:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:14])=[CH:21][CH:20]=2)[N:23]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: NCCN1CCCC1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(C(=O)NCCN3CCCC3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 2-pyrrolidin-1-yl-ethylamine in DCE was added trimethyl aluminum (1.03 mmol, 0.51 mL of 2N solution in DCM). After the reaction was stirred at ambient temperature for 30 minutes, a solution of 4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)phenyl]ureido}pyrazol-1-yl}benzoic acid methyl ester (100 mg, 0.21 mmol) in DCE was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with two drops of water, dried over MgSO4, filtered, and evaporated at reduced pressure. Purification using MPLC (eluting with 15% NH3 in MeOH (2N)/EtOAc) afforded 34 mg (29%) of the title compound. 1H-NMR (acetone-d6) δ 8.43 (d, J=9.0 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 6.84 (d, J=4.0 Hz, 2H), 6.48 (s, 1H), 3.52 (t, J=7.5 Hz, 2H), 2.67 (t, J=3.0 Hz, 2H), 2.50 to 2.64 (m, 4H), 1.70 to 1.72 (m, 4H), 1.31 (s, 9H); MS LC-MS [M+H]+=568, RT=2.48 min.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.[Br:15]N1C(=O)CCC1=O>C(O)(=O)C>[Br:15][C:9]1[CH:8]=[CH:7][C:6]2[O:2][CH2:3][CH2:4][C:5]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: NCCCc1cccc2c1CCO2
Agent: Cl
Solvent: CC(=O)O
Product: NCCCc1c(Br)ccc2c1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the free base (200 mg) liberated from 3-(2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride and N-bromosuccinimide (215 mg) in acetic acid (5 ml) was stirred at room temperature overnight. The solution was evaporated to dryness and the residue taken up in water, basified to pH9-10 with 2N sodium hydroxide and extracted with ethyl acetate. The extracts were dried and evaporated to give the title compound (256 mg) as a pale yellow oil. Tic SiO2 (Dichloromethane/methanol/0.880 ammonia 75:8:1) Rf 0.53
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1cncnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cncnc2)CC1
Yield: 8 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), pyrimidine-5-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:5](OC)=[O:6].[NH3:21]>CO>[CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:6])[NH:21][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:13]2
Reactant: COC(=O)c1c(C#Cc2ccccc2)ccnc1OC
Reactant: N
Solvent: CO
Product: COc1nccc2cc(-c3ccccc3)[nH]c(=O)c12
Temperature: 115 °C

Procedure:
Methyl 2-methoxy-4-(phenylethynyl)nicotinate (100 mg, 0.37 mmol) is dissolved in 7% NH3 in MeOH (3 mL) and heated at 115° C. in a sealed tube for 24 hours. The reaction mixture is cooled to 0° C. and the cyclized product is crystallized out. The compound is collected by filtration and dried after washing with hexanes. MS m/z 253.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Under an argon atmosphere, a solution of 4-methoxyphenol (15.7 g, 0.126 mol) in dimethylformamide (50 mL) was added slowly to a stirred suspension sodium hydride (3.6 g of a 80% suspension in mineral oil, 0.125 mol) in dimethylformamide (100 mL) at 3-7° C. The ice-bath was removed and the resulting mixture was stirred for 2 h at room temperature. A solution of 3,5-dibromopyridine (20 g, 0.083 mol) in dimethylformamide (120 mL) was added to the mixture, which was then heated to 100° C. for 36 h, then cooled to room temperature and poured into a mixture of water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (3×100 mL) and then brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation to give 22.5 g of an orange oil, which was purified by column chromatography, with cyclohexane/ethyl acetate (95/5, v/v) as eluant. Selected fractions containing the product were concentrated via rotary evaporation to give 18.8 g (81%) of a colorless oil.
Reaction SMILES: O.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].O1C=CC2C([O:17][CH2:18][C@@H:19]([OH:42])[CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]3)=CC=CC1=2.[O:43]1[CH2:45][C@H:44]1[CH2:46][O:47][C:48]1[C:53]2[O:54][CH:55]=[CH:56][C:52]=2[CH:51]=[CH:50][CH:49]=1>CO>[OH2:4].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[O:54]1[CH:55]=[CH:56][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([O:17][CH2:18][C@@H:19]([OH:42])[CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:25][CH2:26]3)[C:53]1=2.[O:54]1[CH:55]=[CH:56][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([O:47][CH2:46][C@@H:44]([OH:43])[CH2:45][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]3)[C:53]1=2.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4]
Reactant: c1cc(OC[C@@H]2CO2)c2occc2c1
Reactant: CN(C)CCCc1c(C2CCN(C[C@H](O)COc3cccc4occc34)CC2)sc2ccccc12
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: CN(C)CCCc1c(C2CCN(C[C@H](O)COc3cccc4ccoc34)CC2)sc2ccccc12
Yield: 39.9 %

Procedure:
A solution 4-(3-(3-dimethylaminopropyl)benzo[b]thiophen-2-yl)piperidine (0.075 g, 0.248 mmol, prepared in example 15) and (S)-(+)-7-(oxiranylmethoxy)benzo[b]furan (0.047 g, 0.248 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/10% methanol/1% ammonium hydroxide in dichloromethane gradient elution) to give the title compound as a yellow oil (0.039 g, 32%). The oxalate was prepared to give the title compound. FDMS m/e=493 (M++1 of free base). C29H36N2O3S.C2H2O4.0.5H2O
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH:12]1[N:25]([CH3:26])[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15](=[O:27])[N:14]([CH3:28])[CH2:13]1>>[CH3:26][N:25]1[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15](=[O:27])[N:14]([CH3:28])[CH2:13][CH:12]1[CH2:11][CH2:10][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Product: CN1CC(CCN(C)c2ccccc2)N(C)c2nc3ccccc3n2C1=O
Temperature: 60 °C

Procedure:
To 15 mL of N-methylaniline was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one. The reaction was heated at 60° C. for 1.5 hr, then 100° C. for ~48 hr. The N-methylaniline was removed by distillation. The residue was dissolved in 100 mL of CH2Cl2, washed with 2×100 mL of 1N NaOH and dried over Na2SO4. The organic phase was filtered and concentrated by rotary evaporation. The residue was then heated to 100° C., 0.5 mm Hg to remove any residual starting amine. The crude syrup was crystallized from toluene/iso-octane to afford 2.0 g (55%) of white analytically pure crystals, mp 74°-90° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:29]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[CH2:4][CH2:3]1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NCCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.2 g, 3.1 mmol) and phenylacetaldehyde (0.06 ml, 0.52 mmol) in DCE (15 ml) was added triethylamine (0.066 ml, 0.47 mmol) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 30 minutes, after which time sodium triacetoxy borohydride (0.1 g, 0.47 mmol) was added portion wise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for a further 2 hours before being concentrated under vacuum. The resulting residue was purified by Prep HPLC to afford the title compound (8 mg, 7% yield) as an off-white powder.