Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O:22]CC)=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.O.[Li+:26].[OH-]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+:26]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.239 g, 0.719 mmol) in THF (3 mL) was added H2O followed by LiOH (0.0344 g, 1.44 mmol) and the reaction was stirred at ambient temperature overnight. The reaction was transferred to a sealed tube and heated to 100° C. for 8 hours. The reaction mixture was concentrated providing 0.230 g of the crude desired product as a pale yellow foam, which was used directly in the subsequent step.
Reaction SMILES: CCCC[Sn]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(CCCC)CCCC.Cl[C:21]1[N:26]=[C:25]2[S:27][C:28]([CH3:30])=[CH:29][C:24]2=[CH:23][C:22]=1[C@@H:31]([N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43])[CH3:32]>O1CCOCC1.C(OCC)(=O)C>[CH3:30][C:28]1[S:27][C:25]2=[N:26][C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[C:22]([C@@H:31]([N:33]3[C:34](=[O:43])[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]3=[O:42])[CH3:32])[CH:23]=[C:24]2[CH:29]=1
Reactant: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(Cl)nc2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)nc2s1
Temperature: 100 °C

Procedure:
In a reaction vessel was combined 2-(1,1,1-tributylstannyl)pyridine (0.124 ml, 0.370 mmol), tetrakis triphenylphosphine(0) (35.6 mg, 0.031 mmol), (S)-2-(1-(6-chloro-2-methylthieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (110 mg, 0.308 mmol) in dioxane (3 mL). The reaction was heated to 100° C. for 2 d, cooled to rt, and diluted with ethyl acetate. The organic phase was washed with NaHCO3 and brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography afforded (S)-2-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 8.64 (ddd, J=4.7, 1.8, 0.8 Hz, 1H), 7.72 (td J=7.8, 2.0 Hz, 1H), 7.67 (m, 3H), 7.62 (m, 2H), 7.29 (ddd, J=7.4, 4.9, 1.6 Hz, 1H), 6.98 (q, J=1.4 Hz, 1H), 6.30 (q, J=7.0 Hz, 1H), 2.60 (d, J=1.2 Hz, 3H), 1.97 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([F:21])=[CH:11][C:10]=2[O:22]C)=[C:4]([F:27])[CH:3]=1.Br.CC(O)=O>>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C:12]([F:21])=[CH:11][C:10]=2[OH:22])=[C:4]([F:27])[CH:3]=1
Reactant: COc1cc(F)c(N2CCOCC2)cc1C(=O)NCc1ccc(Br)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Br)cc1F)c1cc(N2CCOCC2)c(F)cc1O
Temperature: 25 °C
Yield: 7.8 %

Procedure:
A solution of N-(4-Bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-morpholin-4yl-benzamide (0.94 g, 24.1 mmol) in a 25% HBr/AcOH solution (25 mL) was heated to 100° C. for 6 h, cooled to room temperature and extracted with ethyl acetate. The crude product was filtered through a short pad of silica and concentrated to give the solid N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-morpholin-4-yl-benzamide (0.8 g, 88%): 1H NMR (DMSO-d6 300 MHz) δ 12.4 (s, 1 H), 9.34 (br s, 1 H), 8.12 (s, 1 H), 8.05 (d, J=8.1 Hz, 1 H), 7.72 (d, J=4.5 Hz, 1 H), 7.56 (t, J=8.1 Hz, 1 H), 7.47 (d, J=9.6 Hz, 1 H), 6.69 (d, J=13.2 Hz, 1 H), 4.56 (d, J=6 Hz, 2 H), 3.65 (br d, J=3 Hz, 4 H), 2.84 (br d, J=3 Hz, 4 H).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[Se:29][C:28]([CH:30]=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.O.Cl>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[Se:29][C:28]([CH:30]=[CH:1][CH3:2])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCOc1ccc(-c2ccc(-c3ccc(C=O)[se]3)cc2)c(F)c1F
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC=Cc1ccc(-c2ccc(-c3ccc(OCCC)c(F)c3F)cc2)[se]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.70 g (12.5 mmol) of ethyltriphenylphosphonium bromide are initially introduced in 50 ml of THF at 0° C., and 1.40 g (12.5 mmol) of potassium tert-butoxide dissolved in 30 ml of THF are added. After 1 h, 4.2 g (10.4 mmol) of 5-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene-2-carbaldehyde in 100 ml of THF are added, and the batch is stirred at RT for 18 h. Water and 2 N hydrochloric acid are added to the mixture, and the batch is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)-5-propenylselenophene is obtained as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:26]1C=CC=CC=1>>[NH2:26][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:13][CH3:14])[C:2]=2[Cl:1])[CH:7]=[CH:8][N:9]=1
Reactant: c1ccncc1
Reactant: COc1ccc2cc[n+]([O-])cc2c1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc2ccnc(N)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.3 g of 8-chloro-7-methoxyisoquinoline-N-oxide in 40 ml of pyridine was added 1.4 g of p-toluenesulfonyl chloride, and the mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure, 20 ml of ethanolamine was added to the resultant residue, and then the mixture was stirred for further 3 hours. The reaction mixture was poured into water, and the crystalline precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 0.8 g of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]C(O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH2:20].[OH-].[Na+]>C(COC)OC>[NH2:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][OH:20]
Reactant: NCC(CC(=O)O)c1ccccc1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: NCC(CO)c1ccccc1

Procedure:
For the preparation of the alcohols VI used in Examples (3a) and (3b). 10 g of 3-amino-2-phenylpropanecarboxylic acid in 150 ml of monoglyme were stirred with 3 g of LiAlH4 for 20 hrs. Then, 12 ml of water and 3 ml of 10% sodium hydroxide solution were slowly added thereto. The mixture was filtered and the filtrate was again evaporated with toluene. There was obtained 8.4 g of β-(aminomethyl)-phenethyl alcohol.
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH:24]([OH:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:42]I>O1CCCC1>[C:3]([O:22][CH2:23][CH:24]([O:41][CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCCCCCCCCCCCCCCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred suspension of sodium hydride (2.40 g, 60% oil dispersion, washed with dry petroleum ether) in dry tetrahydrofuran (40 ml) was portionwise added (rac)-1-O-trityl-1,2-octadecanediol (12.2 g) at ambient temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of methyl iodide (13.1 g) in dry tetrahydrofuran (40 ml) was dropwise added during a period of 45 minutes. After stirring for 3.5 hours at the same temperature, the mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of diethyl ether and 0.5N aqueous sulfuric acid. The separated organic layer was dried and evaporated under reduced pressure. The residue was triturated in petroleum ether to remove impurities by filtration. The filtrate was evaporated to yield 9.8 g of (rac)-1-O-trityl-2-O-methyl-1,2-octadecanediol.
Reaction SMILES: [Mg].Br[CH:3]([CH2:5][CH2:6][CH3:7])[CH3:4].[CH3:8][C:9](=[CH:12][CH2:13][CH3:14])[CH:10]=[O:11].[Cl-].[NH4+]>CCOCC>[CH3:4][C:3]([CH:10]([OH:11])[CH:9]([CH3:8])[CH2:12][CH2:13][CH3:14])=[CH:5][CH2:6][CH3:7]
Reactant: CCCC(C)Br
Reactant: CCC=C(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(C)CCC
Temperature: 10 °C

Procedure:
28.3 g (1.18 g atoms) of magnesium in 200 ml of ether are placed in an apparatus which is customary for Grignard reactions. While stirring and under a protective gas atmosphere (nitrogen) there are subsequently added dropwise 178.1 g (1.18 mol) of 2-bromopentane in 500 ml of absolute ether so that, after initiation of the reaction, the ether constantly boils slightly. After completing the addition, the mixture is held at reflux temperature for a further 30 minutes, then cooled to 10° C. and a solution of 96.1 g (0.98 mol) of 2-methyl-2-pentenal in 300 ml of ether is added dropwise during 30 minutes so that the reaction temperature during the addition lies between 10° and 20° C. In order to complete the reaction, the mixture is refluxed for 1 hour, then the Grignard complex is decomposed with saturated ammonium chloride solution and ice, the supernatant ethereal solution is washed with saturated sodium chloride solution and subsequently dried. After evaporating the solvent, there remain behind 176 g of crude product, which are fractionally distilled. There are thus obtained 119 g (71.4%) of olfactorily good 4,6-dimethyl-3-nonen-5-ol of boiling point 92° C./12 mm Hg.
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>O>[C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: N[C@@H]1CCNC1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: N[C@H]1CCNC1
Temperature: 80 °C

Procedure:
To the filtrate obtained in the above crude (3R)-3-aminopyrrolidine D(-)-tartrate is added a solution of L(+)-tartaric acid (25 g) in water (50 ml), and the precipitated crystals are separated by filtration. The product is dissolved in a 20% aqueous sodium hydroxide solution (50 ml) and thereto is added acetone (300 ml), and the precipitated crystals are removed by filtration. To the filtrate is added a solution of L(+)-tartaric acid (20 g) in water (40 ml). The precipitated crystals are separated by filtration and dissolved in water (30 ml), and thereto is added sodium hydroxide (300 g). The mixture is extracted with ether (300 ml) three times. Ether is distilled off under reduced pressure, and to the residue is added a solution of L(+)-tartaric acid (5.5 g) in water (25 ml), and the mixture is heated at 80° C. To the mixture is added methanol (40 ml), and the mixture is gradually cooled till room temperature. The precipitated crystals are separated by filtration and recrystallized from a mixed solvent of methanol:water (1:1) to give (3S)-3-aminopyrrolidine L(+)-tartrate (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29]CC4C=CC(Cl)=CC=4Cl)[C@@H:15]([O:16]CC4C=CC(Cl)=CC=4Cl)[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:15]([OH:16])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a solution of the compound from Step A (0.87 g, 0.9 mmol) in dichloromethane (30 mL) at −78° C. was added boron trichloride (1M in dichloromethane, 9.0 mL, 9.0 mmol) dropwise. The mixture was stirred at −78° C. for 2.5 h, then at −30° C. to −20° C. for 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) (9 mL) and the resulting mixture stirred at −15° C. for 30 min., then neutralized with aqueous ammonia at 0° C. and stirred at rt for 15 min. The solid was filtered and washed with CH2Cl2/MeOH (1/1, 50 mL). The combined filtrate was evaporated, and the residue was purified on a silica gel column (5×5 cm) using CH2Cl2 and CH2Cl2/MeOH (40/1 and 30/1) gradient as the eluent to furnish the desired compound (0.22 g) as a colorless foam.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:11][CH2:10][C:9]2=[O:25])[CH2:4][CH2:3]1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:30]([O:29][C:27]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:11][CH2:10][C:9]2=[O:25])[CH2:6][CH2:7]1)=[O:28])[CH3:31]
Reactant: CN1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A solution of 98 mg (0.29 mmol) of 1,3-dihydro-1-(1-methyl-4-piperidinyl)-5-phenylbenzodiazepin-2-one 3, 0.084 ml (0.29×3 mmol) of ethyl chloroformate and 54.3 mg (0.29×2.2 mmol) of sodium hydrogencarbonate in 5 ml of benzene is refluxed under heating for 7 hours. The reaction mixture is poured into ice water and extracted with methylene chloride. The organic layer is washed with water dried over anhydrous magnesium sulfate and concentrated to give 114 mg of 1-(1-ethoxycarbonyl-4-piperidinyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 12 as powders. The yield is 100%.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[C:11]([F:15])[CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[C:11]([F:15])[CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:21][CH3:22])=[O:2]
Reactant: CCO
Reactant: O=C(O)C=Nc1cccc(F)c1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Nc1cccc(F)c1C(=O)O
Temperature: 25 °C

Procedure:
10.6 g of N-carboxymethylene-6-fluoro-anthranilic acid having a purity of 73% (corresponding to 39.6 mmol) are suspended in 25 ml of ethanol, 0.98 g (9.6 mmol) of concentrated sulfuric acid are added and the reaction mixture is heated under reflux for 6 hours. It is cooled to room temperature and the product which has precipitated out is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nn(C(C)(C)C)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nn(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of ethyl 1-tert-butyl-4-formyl-1H-pyrazole-3-carboxylate (2.87 g, 12.8 mmol) in ethanol (50 mL) was added sodium borohydride (0.97 g, 25.6 mmol) in one portion. After stirring for 30 minutes at room temperature the mixture was quenched with 1 N aqueous hydrochloric acid (100 mL), stirred for 15 minutes, and then neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2×150 mL), the combined organics then dried over sodium sulfate, filtered and concentrated to yield ethyl 1-tert-butyl-4-(hydroxymethyl)-1H-pyrazole-3-carboxylate (2.57 g) as a clear oil. +APCI (M+Na) 249.2; 1H NMR (400 MHz, CDCl3, δ): 7.49 (s, 1H), 4.65 (d, J=6.8 Hz, 2H), 4.43 (q, J=7.2 Hz, 2H), 3.62 (t, J=6.9 Hz, 1H), 1.59 (s, 9H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16]O)[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:19]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][Br:19])[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)Cn1c(CO)nc2c(Cl)ncnc21
Solvent: ClCCl
Product: CC(C)(C)Cn1c(CBr)nc2c(Cl)ncnc21

Procedure:
A solution of 6-chloro-8-hydroxymethyl-N9-neopentylpurine (1 mmol) in methylene chloride was treated with phosphorus tribromide (1 mmol) at 25° C. for 6 h. Extraction and chromatography afforded 6-chloro-8-bromomethyl-N9-neopentylpurine as a white solid. TLC: Rf=0.64, 25% EtOAc-hexane.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]1([CH2:30][N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:29][O:28][CH2:27]1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][C:26]6([CH3:25])[CH2:27][O:28][CH2:29]6)[CH:35]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][NH:17][C:16]1=[O:19])([CH3:22])[CH3:21]
Reactant: CC(C)n1c(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n[nH]c1=O
Reactant: CC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Product: CC(C)n1c(-c2nc3c(s2)CCOc2cc(-c4cnn(CC5(C)COC5)c4)ccc2-3)n[nH]c1=O

Procedure:
Similarly to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one was reacted with 1-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Purification of the crude reaction mixture by reverse phase HPLC gave 456. LCMS: 479.1
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH2:15][N:14]4[CH2:13][CH2:12][CH:11]([C:6]2=3)[CH2:17][CH2:16]4)=[CH:21][CH:20]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1ccc(Cl)cc1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 1-chloro-4-vinylbenzene (277 mg, 2.0 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.52-1.66 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (s, 3H), 2.85-3.03 (m, 5H), 3.05-3.19 (m, 2H), 4.15 (s, 2H), 4.32 (t, J=7 Hz, 2H), 6.82-6.96 (m, 3H), 7.06-7.22 (m, 4H); MS (DCI/NH3) m/z 365 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][O-].[K+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CC(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:9]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1ncc(F)cc1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(Br)cc(F)cn12
Temperature: 90 °C
Yield: 79.8 %

Procedure:
A mixture of 3-bromo-5-fluoropyridin-2-amine (3.0 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (7.4 g), sulfuric acid (0.84 mL) and 2-propanol (60 mL) was heated at 90° C. for 3 days. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol, and the obtained solid was collected by filtration to give the title compound (3.6 g).
Reaction SMILES: [CH:1]1(Br)[CH2:4][CH2:3][CH2:2]1.[Mg].[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:10]([NH2:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[F:7])[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1F
Reactant: BrC1CCC1
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(c1ccccc1F)C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
One third of a solution of cyclobutyl bromide (5.0 g, 41.3 mmol) in anhydrous tetrahydrofuran (24 mL) was stirred with magnesium (1.11 g, 46.3 mmol) under reflux. The remaining solution was added dropwise over a period of 15 minutes, and the stirring at reflux continued for 30 min. To the obtained solution 2-fluorobenzonitrile (1.2 g) in THF (15 ml) was added dropwise at 0° C. The mixture was stirred for 5.5 h at 0° C. followed by addition of methanol (30 ml) and sodium borohydride (1.13 g). The reaction mixture was stirred for 16 hours at ambient temperature and concentrated. The residue was partitioned between chloroform (3×100 ml) and water, and the pH was adjusted to 1. The mixture was extracted with chloroform. The aqueous phase was adjusted to pH=10, and extracted with chloroform (3×100 ml). The combined organic layers were dried, evaporated and purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1/1) to afford the title amine (0.45 g, yield: 7.9%) 1H NMR (CD3OD, 400 MHz) 7.49-7.38 (m, 2H), 7.30-7.15 (m, 2H), 4.50 (d, J=10.4 Hz, 1H), 3.00-2.90 (m, 1H), 2.29-2.21 (m, 1H), 2.09-1.71 (m, 5H).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)=[CH:2][CH3:3].[OH-].[Na+].O>C(O)C>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[CH:2][CH3:3]
Reactant: CC=CC1CCC(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC=CC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 g of ethyl 4-propenylcyclohexanecarboxylate from Example 2, 38 g of sodium hydroxide, 215 ml of water and 1075 ml of ethanol were combined and stirred overnight at RT. Conventional work-up gave 4-propenylcyclohexanecarboxylic acid as an E/Z isomer mixture.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].S(OCC)(O[CH2:17][CH3:18])(=O)=O>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:17][CH3:18])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: Brc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(Br)nc2ccccc21
Yield: 91.9 %

Procedure:
To a flask were added 4 g 2-bromo-1H-benzimidazole and 60 ml tetrahydrofuran, and the mixture was cooled to 10 C. To this mixture was added 1.2 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 4.7 g of diethyl sulfate were added. The reaction mixture was heated to 40 C for several hours, then cooled to 22 C and quenched with 100 ml water. The product was extracted twice with 50 ml ethyl acetate and following removal of the solvent, the product was purified by silica gel chromatography using a gradient from 100% hexane to 25% ethyl acetate in hexane. An oil was obtained that crystallized on standing which was dried resulting in 4.2 g of a white solid.