Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:16][S:17]([O:15][CH2:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7.96 g of {(3S)-1-(tert-butoxycarbonyl)-3-piperidyl}methanol in 150 ml of chloroform, 3.4 ml of methanesulfonyl chloride and 6.7 ml of triethylamine were added under cooling with ice, followed by an hour's stirring at room temperature. The reaction liquid was distilled off under reduced pressure, diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution was added, followed by 1.5 hours' stirring. Thereafter the reaction liquid was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. Distilling the solvent off, 10.50 g of the title compound was obtained.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11](OCC)=[O:12])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=O)C.[BH4-].[Na+]>C1COCC1.CO>[C:19]([O:18][C:16]([N:8]1[CH2:7][C@@H:6]([CH2:4][OH:3])[C@H:10]([CH2:11][OH:12])[CH2:9]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1

Procedure:
To a stirred solution of (±)-trans-pyrrolidine-1,3,4-tricarboxylic acid 1-tert-butyl ester 3,4-diethyl ester (15.85 mmol, 5 g) in a mixture of THF (50 mL) and methanol (50 mL) was added NaBH4 (4 g) portions wise over a period of 1 h. The volatiles were removed under reduced pressure. To the residue was added water and extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with ethyl acetate to provide (±)-trans-3,4-bis-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1Nc1ccccc1
Yield: 98.9 %

Procedure:
A solution of 4-bromo-2-fluoro-1-nitrobenzene (10.0 g, 45 mmol), diisopropanylethylamine (15.8 ml, 90 mmol) and aniline (5.0 ml, 54 mmol) in 100 ml 1-methylpyrrolidin-2-one (NMP) was heated at 100° C. for 16 hours. The solution was cooled to room temperature and added 1,000 ml water. The result red precipitate was filtered and washed with water (100 ml), dried under high vacuum to obtain 5-bromo-2-nitro-N-phenylbenzenamine (10.3 g, 77%). A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.50 g, 1.7 mmol) and piperidine (0.67 ml, 6.8 mmol) in 10 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperidin-1-yl)benzenamine (0.50 g, 100%) was obtained by flash column chromatograph (30% acetyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 1.66 (m, 6H), 3.33 (t, J=5.8 Hz, 4H), 6.34 (dd, J=2.6, 9.7 Hz, 1H), 6.42 (d, J=2.6 Hz, 1H), 7.23-7.46 (m, 5H), 8.14 (d, J=9.7 Hz, 1H), 9.93 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 24.8, 25.4, 48.7, 95.6, 106.4, 124.8, 125.6, 129.4, 130.1, 139.7, 146.0, 156.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=O.[NH2:18]/[C:19](/[CH3:23])=[CH:20]\[C:21]#[N:22]>CC(O)=O.CCOC(C)=O>[C:21]([C:20]1[CH:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][N:7]=[C:6]3[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:3])[NH:18][C:19]=1[CH3:23])#[N:22]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(C=O)cc12
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.4 %

Procedure:
A mixture of 5-formyl-N-methoxy-N-methyl-1H-indazole-3-carboxamide (400 mg, 1.72 mmol) from Synthetic Preparation 6, and 3-aminocrotononitrile (299 mg, 2.12 mmol) in HOAc (5 mL) was kept at 110° C. for 2 hr. After cooling to rt, the reaction mixture was diluted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by flash chromatography to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-methoxy-N-methyl-1H-indazole-3-carboxamide (500 mg, 80.5%) (Cpd. No. 143, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=9.65 (s, 1H), 7.85 (s, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 4.58 (s, 1H), 3.78 (s, 3H), 3.44 (s, 3H), 2.03 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:12][CH2:11][C@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 16F (0.6 g, 1.790 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.299 mL, 2.148 mmol) and MsCl (0.167 mL, 2.148 mmol). The reaction was stirred at rt for 2 h. The solvent was removed and residue was redissolved in EtOAc. The solution was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-40% ETOAc/hexanes) to give 24A (0.74 g, 1.790 mmol, 100% yield) as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.40 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.39-4.59 (m, 4H) 3.69 (d, J=5.81 Hz, 2H) 3.52-3.62 (m, 1H) 2.85 (s, 3H) 2.33 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>ClCCl>[C:1]1([N:7]=[C:8]([Cl:20])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)Nc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(Cl)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-phenylpropionamide(7.46 g, 0.05 mol) and pyridine(13.8 g, 0.18 mol) were dissolved in dichloromethane(300 g) , and the mixture was cooled to 0° C. And then phosphorus oxychloride(8.43 g, 0.05 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20° C.) for 2 hours to produce N-phenylpropionimidoylchloride.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:40]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.3 %

Procedure:
4-Amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-pyridyl)benzamide (225.3 mg, 0.50 mmol) was dissolved in methylene chloride (2.0 ml) to which were subsequently added pyridine (0.05 ml, 0.62 mmol) and benzoyl chloride (0.09 ml, 0.77 mmol). After 14 hours of stirring at room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The resulting organic layer was washed with saturated sodium chloride aqueous solution and water in that order, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) and recrystallization (ethyl acetate-ether) to obtain 196.3 mg (70.6%) of the title compound in a light brown powder form.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH3:12]>O1CCOCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH2:12])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: N
Solvent: C1COCCO1
Product: Nc1ccc2nnc(Cl)n2n1

Procedure:
A mixture of 190 mg of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine and 1 cm3 of aqueous ammonia at 35% in 1 cm3 of dioxane, in a sealed tube, is heated at between 70° C. and 90° C. for 3 h. The precipitate formed is filtered off, to give 156.4 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([Br:28])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:11][C:12]2[C:17]([Br:18])=[C:16]([Br:19])[C:15]([Br:20])=[C:14]([Br:21])[C:13]=2[Br:22])[CH2:9][O:8][CH2:7]1.O.S(=O)(=O)(O)[OH:31]>O1CCOCC1>[Br:18][C:17]1[C:12]([O:11][CH2:10][C:6]([CH2:5][O:4][C:3]2[C:2]([Br:1])=[CH:26][C:25]([Br:27])=[CH:24][C:23]=2[Br:28])([CH2:7][OH:8])[CH2:9][OH:31])=[C:13]([Br:22])[C:14]([Br:21])=[C:15]([Br:20])[C:16]=1[Br:19]
Reactant: Brc1cc(Br)c(OCC2(COc3c(Br)c(Br)c(Br)c(Br)c3Br)COC2)c(Br)c1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: OCC(CO)(COc1c(Br)cc(Br)cc1Br)COc1c(Br)c(Br)c(Br)c(Br)c1Br

Procedure:
A mixture of the oxetane derivative of Example 2 (47.5 g., 0.053 moles), dioxane (290 ml.), water (10 ml.) and 1 g. of conc. sulfuric acid was stirred and refluxed 22 hours. The cooled reaction mixture was poured into 1.5 liters of water. A gummy solid formed which became crystalline when heated with dioxane. This product was recrystallized twice from dioxane, yielding 19.4 g. of the desired product which had a melting point of 184°-187° C.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.ClC1N(CC=C)[C:27]2C(=O)NC(=O)N(CCC3CC3)[C:22]=2N=1>>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH:18]3[CH2:27][CH2:22]3)[C:4]=2[N:3]=1
Reactant: CCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC1CC1
Product: N#CCn1c(=O)c2[nH]c(Cl)nc2n(CCC2CC2)c1=O

Procedure:
Prepared as (8-chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile (example 23) using 8-chloro-3-(2-cyclopropylethyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[OH2:9].CC[O:12]CC>>[C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[CH3:1][C@@H:2]([OH:12])[C@H:3]([OH:9])[CH3:4]
Reactant: O
Reactant: CCOCC
Agent: N[C@@H]1CCCC[C@H]1N
Product: C[C@@H](O)[C@@H](C)O
Temperature: 25 °C

Procedure:
1.28 g (11.2 mmol) of (1R,2R)-(-)-1,2-cyclohexanediamine of α!D20 =-36.7° (c 4.1, H2O) and 1.00 g (11.1 mmol) of dl-threo-2,3-butanediol were added to 2 ml of ether and then heated/dissolved therein, and the solution was cooled to room temperature. Afterward, the precipitated crystals were collected by filtration and then recrystallized from 2 ml of ether twice to obtain 1.00 g of (1R,2R)-(-)-1,2-cyclohexanediamine·(2R,3R)-(-)-2,3-butanediol. Physical properties of the product are as follows.
Reaction SMILES: C([O:4][CH:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]([CH2:32][OH:33])[CH:19]=1)[CH2:6][NH:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][N:11]1[CH:15]=[N:14][N:13]=[CH:12]1)(=O)C.[H][H]>[Pd].CO>[CH3:17][C:8]([NH:7][CH2:6][CH:5]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:32][OH:33])[CH:19]=1)[OH:4])([CH3:16])[CH2:9][CH2:10][N:11]1[CH:15]=[N:14][N:13]=[CH:12]1
Reactant: CC(=O)OC(CNC(C)(C)CCn1cnnc1)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(CCn1cnnc1)NCC(O)c1ccc(O)c(CO)c1

Procedure:
5 g of 1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-ethanol acetate are hydrogenated with 0.5 g of palladium on charcoal (5%) in 100 mL methanol. After the theoretically calculated amount of hydrogen has been taken up the catalyst is filtered off and the filtrate is evaporated down. The residue is dissolved in 10 mL ethanol and seeded. Then the product that crystallises out is suction filtered and washed. Yield: 3.2 g (74%, acetate); m.p.=125-127° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:36]>CO>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([NH2:36])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
A solution of ethyl 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinate (230 mg, 0.288 mmol) in MeOH (5 mL) was purged with ammonia gas for 5 minutes at −10° C. The reaction mixture was heated in a sealed tube at 70° C. for 12 h. The volatile components were removed under reduced pressure and the resulting residue was purified by HPLC (Condition 20 as described in general methods) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinamide (50.0 mg, 39.8%) as a yellow solid. LCMS (Condition 2): retention time 1.90 min, [M+1]=433.0. HPLC (Condition 25): retention time=5.20 min, purity 98.63%. 1H NMR (400 MHz, DMSO-d6) δ 4.66 (d, J=4.0 Hz, 2 H), 6.32 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.22-7.24 (m, 1 H), 7.28 (d, J=7.6 Hz, 1 H), 7.51-7.60 (m, 5 H), 7.68-7.73 (m, 3 H), 7.84 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 7.93 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.22-8.24 (m, 1 H), 8.28 (br s, 1 H), 8.51 (t, J=2.0 Hz, 1 H), 8.99 (d, J=2.0 Hz, 1H), 9.18 (d, J=2.0 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Brc1nccc2ccccc12
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1nccc2ccccc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 1-bromoisoquinoline (2.06 g, 10 mmol), prepared as described in European Journal of Organic Chemistry 2002, 4181-4184, 2-methoxyphenylboronic acid (2.79 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:18][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)NCCc1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NCCc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a round-bottomed flask, N-[2-(4-acetyl-phenyl)-ethyl]-acetamide (7.23 g, 35.2 mmol) was dissolved in methylene chloride (120 ml), and methanol (60 ml). Tetrabutylammonium tribromide (17.0 g, 35.2 mmol) was added to this solution in one portion, and the mixture was allowed to stir overnight at room temperature. The volatiles were then removed in vacuo to afford an oil, which was then resuspended in 100 ml of methylene chloride and extracted with 125 ml of saturated aqueous sodium bicarbonate. The aqueous extracts were reextracted with methylene chloride (3×100 ml), and the combined organic extracts were then washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by column chromatography (silica gel; methylene chloride to 7% methanol/methylene chloride), and the resulting material was washed with 110 ml of water to afford 8.27 g (83% yield) of pure product as a white solid. LRMS ([M−1]−)=283.0, 284.9.
Reaction SMILES: Cl[S:2]([C:5]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:6]=1[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=[O:4])=[O:3].[NH2:26][C:27]1[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]2[C:30]([C@H:31]3[CH2:41][C@H:32]3[CH2:33][O:34]2)=[CH:29][CH:28]=1>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:5]([S:2](=[O:4])(=[O:3])[NH:26][C:27]2[CH:28]=[CH:29][C:30]3[C@H:31]4[CH2:41][C@H:32]4[CH2:33][O:34][C:35]=3[C:36]=2[C:37]([O:39][CH3:40])=[O:38])=[C:6]([CH:21]=1)[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OCc2cc(F)ccc2S(=O)(=O)Cl)C1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21
Reaction time: 120 h
Yield: 99.5 %

Procedure:
A solution of tert-butyl (S)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate 215, 0.295 g) in DCM (2 mL) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A, 0.11 g) in DCM (2 mL) and the mixture was left at room temperature for 5 days. The mixture was diluted with DCM, washed with 1M hydrochloric acid and filtered through a phase separator. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give tert-butyl (S)-3-[5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa-[c]chromen-5-ylsulfamoyl)benzyloxy]pyrrolidine-1-carboxylate (0.288 g) as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])=[CH:9][C:8]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 61.6 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (19 mg, 0.019 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (18 mg, 0.019 mmol) and cesium carbonate (454 mg, 1.4 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-(2,4,5-trifluoro-phenyl)-quinoline (compound of example 21) (400 mg, 0.93 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (97 mg, 1.11 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (250 mg, 62%). MS: m/z=437 (M+H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].[NH2:28][C:29]1[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:40])[CH:30]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.C(N(C(C)C)CC)(C)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([NH:28][C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:40])[CH:30]=2)=[O:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: COC(=O)c1cc(C)c(N)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a stirred solution of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (670 mg, 1.82 mmol) and methyl 4-amino-2,5-dimethylbenzoate (390 mg, 2.18 mmol) in dichloromethane (3.6 mL) and diisopropylethylamine (0.413 mL) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (829 mg, 2.18 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane containing from 3% to 5% methanol to provide methyl 4-{3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}-2,5-dimethylbenzoate (568 mg, 59% yield). LCMS (10-70) Rt=4.55; [M+H+] found 530.4.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:15][N:16]([CH3:18])[CH3:17])[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2ccc(Br)cc2CN1
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)NCc2cc(Br)ccc21
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a suspension of 7-bromo-1,4-dihydro-2H-isoquinolin-3-one (450 mg, 2 mmol) in 1 mL of N,N-dimethylformamide is added N,N-dimethylformamide dimethylacetal (954 mg, 8 mmol). The reaction mixture is heated in a microwave at 100° C. for 10 min. The reaction mixture is then filtered and washed with N,N-dimethylformamide to give 356 mg of 7-bromo-4-dimethylaminomethylene-1,4-dihydro-2H-isoquinolin-3-one.