Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)=[CH:5]1)[CH2:2][CH3:3].C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+].Cl.[K+].[Br-]>C1COCC1.O>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1C=C(C2=CC(=O)CCC2)CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CCCC(C2=CC(=O)CCC2)C1
Reaction time: 1 h

Procedure:
3-(1-Propyl-1,4,5,6-tetrahydro-pyridin-3-yl)-cyclohex-2-enone (5.0 g, 22.8 mmol) (from b) above) was dissolved in THF (100 mL). At 0° C., acetic acid (1.38 mL, 22.8 mmol) was added followed by introduction of NaBH3CN (1.9 g, 30.0 mmol) in small portions maintaining the temperature. After the addition was complete the mixture was stirred for 1 h at this temperature and then at rt overnight. Work-up by addition of water (50 mL) and saturated aqueous NaHCO3 (50 mL) followed by extraction with dichloromethane (5×50 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by column chromatography (silica, dichloromethane/ethanol 20:1) to give a colorless oil which was converted to the hydrochloride. Recrystallisation from isoprylether gave 4.2 g, 17.5 mmol (77%), mp 184–185° C. IR (KBr) 3396, 2941, 2469, 1667, 1455 cm−1; 1H-NMR (CDCl3) δ 5.83 (s, 1H), 3.85 (d, 2H), 2.29–2.56 (m, 7H), 1.23–2.17 (m, 10H), 0.88 (t, 3H) ppm; 13C-NMR (CDCl3) δ 198.4, 165.1, 123.4, 59.0, 55.6, 51.9, 41.6, 36.0, 27.3, 26.9, 22.8, 21.2, 17.6, 10.2 ppm; MS (EI) m/z 221 (M+).
Reaction SMILES: [C:1](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[C:5]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:6][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1.CN1CCOCC1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCCCCC>ClCCl>[CH2:47]([NH:54][C:1](=[O:29])[O:2][CH2:3][C:4]1[C:5]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:6][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(OCc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NCc1ccccc1)OCc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.4 %

Procedure:
To a solution of the [6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl 4-nitrophenyl carbonate (51 mg, 0.089 mmol) in dichloromethane (1 ml) were successively added N-methylmorpholine (0.020 ml, 0.18 mmol) and benzylamine (0.012 ml, 0.11 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. A fraction obtained from the elution portion with hexane:ethyl acetate=4:1 was concentrated under reduced pressure. The solid thus obtained was washed with diisopropyl ether and collected by filtration, whereby the title compound (33 mg, 0.060 mmol, 68%) was obtained as a white solid.
Reaction SMILES: [NH2:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([N:8]=[C:9]([NH2:11])[NH2:10])#[N:7].[OH2:12]>>[S:2](=[O:4])(=[O:3])([OH:5])[NH2:1].[C:9]([NH:8][C:6]([NH2:7])=[O:12])(=[NH:11])[NH2:10]
Reactant: O
Reactant: N#CN=C(N)N
Agent: NS(=O)(=O)O
Product: N=C(N)NC(N)=O
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Sulfaminic acid (97 g) was added batchwise to a solution composed of 84 g dicyandiamide and 300 ml of water at 80° C. whereby the temperature was not permitted to exceed about 95° C. After addition was complete, the temperature was held at 95° C. for 20 minutes, after which the solution was evaporated using a water-jet vacuum. By this process 189 g (=95% of theoretical) guanylurea sulfamate was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:25])[C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:11](Cl)=[N:10][CH:9]=1>CN(C=O)C.O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:11]([N:1]=[N+:2]=[N-:3])=[N:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(N=[N+]=[N-])c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide (4.4 g, 68 mmol) was added to a suspension of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid methyl ester (26) (13.89 g, 33.8 mmol) in DMF (200 mL) and the mixture allowed to stir at room temperature overnight. The solution was diluted with water (600 mL) and the resulting white precipitate was collected by filtration and washed with water. The solids were dissolved into THF. Two volumes of diethyl ether were added and the organic solution washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to the desired product (27) as a light yellow solid (12.94 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12]>S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc(C)cn1
Temperature: 78 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The reaction is carried out, under nitrogen, in a 1 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor is charged with 5-methylpyrazinecarboxylic acid (100 g), ethanol (300 g) and sulfuric acid (2 g). The contents are refluxed for eight hours at 78° C. The reaction mixture is cooled to ambient temperature and sodium bicarbonate (4 g) is added. About 75% of the solvent is removed under reduced pressure and the resulting suspension is allowed to stand overnight. The solids are filtered and washed with cold methanol (2×80 g). Drying under oven (25 inches of Hg) yielded 101.25 g (84%) of 5-methyl-2-pyrazinecarboxylic acid, ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[O:10][CH:11]=[CH:12][N:13]=1.[O:14]=[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=2)[N:16]1[CH2:29][C:30](O)=[O:31]>>[C:7]([C:4]1[C:3]([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)=[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([F:26])([F:28])[F:27])=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:15]2=[O:14])[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-c1ncco1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1ncco1

Procedure:
The title compound was synthesized from 5-amino-4-(oxazol-2-yl)thiophene-3-carbonitrile (21 mg, 0.11 mmol) and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (30 mg, 0.11 mmol) according to protocol A. The product was purified by HPLC. LCMS method [7], retention time=6.70 min; MS (ESI) 445.0 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.19 (d, J=9.8 Hz, 2H), 7.95-7.80 (m, 3H), 7.85 (d, J=1.8 Hz, 1H), 7.08 (d, J=0.8 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 5.45 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[N:25]=[CH:24][N:23]=[C:22]3[C:14]=2[C:15]2[CH2:16][CH2:17][C:18]4[N:28]([CH2:29][CH2:30]O)[N:27]=[CH:26][C:19]=4[C:20]=2[S:21]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:33][CH2:30][CH2:29][N:28]1[C:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:22]([S:21][C:20]=3[C:19]=2[CH:26]=[N:27]1)=[N:23][CH:24]=[N:25][C:13]=4[O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)cc1
Yield: 54.1 %

Procedure:
This compound was prepared in a similar fashion as described in Example 48 step 5 starting from 2-{6[2-(4-nitro-phenyl)-ethoxy]-4,5-dihydro-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-3-yl}-ethanol (4.2 g, 9.6 mmol), carbontetrabromide (6.37 g, 19.20 mmol), and triphenyl phosphine (5.03 g, 19.20 mmol). The desire product was obtained as a light yellow solid (2.6 g) in 54% yield. LCMS RT=3.55 min; [M+H]+=500.1/502.0.
Reaction SMILES: ICI.[F:4][C:5]1([F:35])[C@@H:22]([O:23]C2CCCCO2)[CH2:21][CH2:20][C@@:19]2([CH3:30])[C:6]1=[CH:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[O:31][CH:32]1[CH2:34][CH2:33]1.Cl>C(OCC)C.O1CCOCC1.[Zn]>[F:4][C:5]1([F:35])[C@@H:22]([OH:23])[CH2:21][CH2:20][C@@:19]2([CH3:30])[C:6]1=[CH:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[O:31][CH:32]1[CH2:33][CH2:34]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: Cl
Agent: [Zn]
Solvent: ICI
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
To a suspension of 0.3 g of zinc dust in 3 ml of diethyl ether is added 50 mg of cuprous chloride. The resulting mixture is refluxed for 30 minutes and then 1.06 g of diiodomethane is added. The resulting solution is refluxed for 30 minutes and 0.3 g of 4,4-difluoro-3β-(2-tetrahydropyranyloxy)-17β-ethenyloxyadrost-5-ene is added. The resulting mixture is refluxed for 16 hours and then diluted with 10 ml of diethyl ether and filtered. The solid which is separated is washed with ethyl acetate (3 times, 50 ml) and the combined filtrate and washings are washed with saturated aqueous ammonium chloride and dried over magnesium sulfate. The solvent is then removed under reduced pressure to leave a residual solid which is crude 4,4-difluoro-3β-(2-tetrahydropyranyloxy)-17β-(cyclopropyloxy)androst-5-ene containing some 17β-(cyclopropyloxy)cycloprop[5,6]androstane product. This material is treated with a catalytic amount of hydrochloric acid in aqueous dioxane to remove the tetrahydropyranyl protecting group. The solvent is then removed under reduced pressure to leave a residual crude solid which is purified by reverse phase high-pressure liquid chromatography to give 4,4-difluoro-17β-(cyclopropyloxy)androst-5-en-3β-ol. The compound has the following structural formula: ##STR4##
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS[C:21]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][N:29]=2)[N:24]=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:21]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][N:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CSc1ncnc2nccnc12
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3nccnc23)CC1

Procedure:
EXAMPLE 86 was prepared from 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester and 4-methylthio-pteridine (4-methylthio-pteridine was prepared according to A. A. Brown, D. J. Brown,h. C. S. Wood, J. Chem. Soc., 1954, 3832–3839): MS (m+1)=379.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:39])[NH:9][C:10](=[O:38])[C@H:11]([N:19](C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:39])[NH:9][C:10](=[O:38])[C@H:11]([NH:19][CH3:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)NN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of N'-((2R)-2-[N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylamino]-3-phenylpropionyl)-N-methylhydrazinecarboxylic acid tert-butyl ester (0.65 g, 1.23 mmol) in methylene chloride (4 ml) was added tris(2-aminoethyl)amine (4 ml) and the mixture was stirred at room temperature for 60 min. Then methylene chloride (50 ml) was added and the mixture was washed with brine (2×20 ml), phosphate buffer (pH=6, 2×20 ml), water (20 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.34 g (90%) of N-methyl-N'-((2R)-2-(methylamino)-3-phenylpropionyl)hydrazinecarboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[NH4+].[Cl-].Cl>C1COCC1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[C:7]2[CH3:12])=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc2[nH]c(C)c(C(C)(C)C(=O)O)c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C(C)(C)C(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-2-methyl-propionic acid (150 mg, 0.611 mmol) in THF (4 mL) was added KHMDS (0.5M solution in toluene; 3.1 mL, 1.55 mmol) and the solution stirred for 20 min at 0° C. 4-Chlorobenzoyl chloride (85.4 uL, 0.672 mmol) was added and the solution allowed to attain ambient temperature. After 30 minutes, satd. aq. NH4Cl soln. was added and the aqueous layer acidified with dil. HCl, extracted with EtOAc, the organic phase dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (0 to 30% acetone:hexanes) to afford 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]-2-methyl-propionic acid as an orange foam. 1H NMR (500 MHz, CDCl3) δ 7.69 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz), 7.08 (1H, d, J=2.4 Hz), 6.91 (1H, d, J=9.0 Hz), 6.66 (1H, dd, J=9.0, 2.4 Hz), 3.74 (3H, s), 2.39 (3H, s), 1.79 (6H, s). LCMS(EI) 386 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH3:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:9])[CH3:10])=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Cc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(Cc1ccc(C)cc1)c1ccccc1
Reaction time: 8 h

Procedure:
1-Phenylacetone (200 mg, 1.49 mmol) was mixed with powdered potassium hydroxide (167 mg, 2.98 mmol) and tetra-n-butylammonium bromide (1 mol %, 5 mg) in a flask without solvent. This mixture was stirred at room temperature for 90 min. before the addition of 1-(chloromethyl)-4-methylbenzene (198 μl, 1.49 mmol). The reaction mixture was then stirred overnight before diluting with water and CH2Cl2. The aqueous layer was separated and neutralized to pH 7 with 2N hydrochloric acid and extracted again into CH2Cl2. The combined organic washes were dried with MgSO4 and concentrated. The crude material was purified by column chromatography on silica gel eluting from 0-10% EtOAc/hexane to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.35 (t, J=7.0 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 7.23 (d, J=7.1 Hz, 2H), 7.05 (d, 7.8 Hz, 2H), 6.98 (d, J=7.8 Hz, 2H), 3.94 (t, J=7.3 Hz, 1H), 3.43 (dd, J=13.9, 7.5 Hz, 1H), 2.91 (dd, J=14, 7.1 Hz, 1H), 2.32 (s, 3H), 2.08 (s, 3H). LC-MS: m/e 239 (M+H)+ (3.61 min).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:33][C:34]1[N:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][N:35]=1.[BH4-].[Na+]>ClCCCl>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]2[CH2:31][C@H:30]2[NH:32][CH2:40][C:37]2[CH:36]=[N:35][C:34]([NH2:33])=[N:39][CH:38]=2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ncc(C=O)cn1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncc(CN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)cn1
Reaction time: 20 h
Yield: 24.9 %

Procedure:
Sodium triacetoxy borohydride (883 mg, 4.166 mmol) was added slowly at 0° C. to a solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine (Intermediate B, 500 mg, 2.083 mmol), 2-aminopyrimidine-5-carbaldehyde (256 mg, 2.083 mmol) in DCE (10 mL) and stirred for 20 h. After completion, the solvent was evaporated. The residue was dissolved in Methanol (15 mL), NaBH4 (237 mg, 6.249 mmol) was added slowly at 0° C. and stirred for 3 h. After completion, the solvent was evaporated, the residue was dissolved in ice water (20 mL) and extracted with EtOAc (2×20 mL) The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by prep HPLC to afford 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine (180 mg, 25%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.85 (q, 1H), 0.90 (quin, 1H), 1.73 (m, 1H), 2.07 (m, 1H), 2.75 (brs, 1H), 3.53 (s, 2H), 5.04 (s, 2H), 6.46 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H), 7.33 (m, 1H), 7.42 (m, 4H), 8.11 (s, 2H). Mass (M+H): 347.3
Reaction SMILES: [OH:1][CH:2]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][O:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.CNN.C(OCC)C>ClCCl>[NH2:5][O:4][CH2:3][CH:2]([OH:1])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(O)CON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)C(O)CON
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a solution of 2-(2-hydroxy-3,3-dimethyl-butoxy)-isoindole-1,3-dione (1.47 g, 5.60 mmol) in dichloromethane (20 mL) cooled to 0° C. was added methylhydrazine (0.31 mL, 5.90 mmol). The white suspension was allowed to stir for 16 hours at room temperature. Diethyl ether (50 mL) was added and the solids were removed by filtration. The filtrate was concentrated, diluted with diethyl ether and the solids were removed by filtration. This procedure was repeated twice more and the final filtrate was concentrated to provide the desired product as a yellow liquid (0.643 g, 86%). 1H NMR (400 MHz, CDCl3) δ 4.87 (br s, 2H), 3.85 (q, 1H), 3.58 (q, 2H), 0.93 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]1[O:15][CH3:16])(C)(C)C.Cl>>[CH3:16][O:15][C@H:9]1[C@H:8]([NH2:7])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]1
Reactant: CO[C@@H]1CN(C)CC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Product: CO[C@@H]1CN(C)CC[C@H]1N
Reaction time: 1 h

Procedure:
Tert-butyl((3R,4R)-3-methoxy-1-methyl-piperidin-4-yl)-carbamate (3.01 g) is combined with HCl (4 molar in dioxane, 25 mL). After 1 h the reaction mixture is freed from the solvent in vacuo and used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=O)[CH:17]=1.CC1ON=C(C2C=CC=CC=2)C=1C1N=C[N:42]([C:44]2[CH:52]=[CH:51][C:47](C(O)=O)=CC=2)C=1>>[CH:52]1([CH2:44][NH:42][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)[CH:19]=2)[CH2:47][CH2:51]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NCC3CC3)c2)cn1
Yield: 43 %

Procedure:
As described for Example 71c, 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol), instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid was converted to the title compound (50 mg, 43%) which was obtained as an off-white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:30])=[O:29].Br[C:33]1[S:37][C:36]([S:38]([N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14]([C:33]4[S:37][C:36]([S:38]([N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)(=[O:39])=[O:40])=[CH:35][CH:34]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:30])=[O:29]
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)C(C)(C)C4)c3c2)OC1(C)C
Reactant: O=S(=O)(c1ccc(Br)s1)N1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(S(=O)(=O)N5CCCC5)s4)cc23)CCS1(=O)=O
Temperature: 100 °C
Yield: 21.4 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (75 mg, 0.17 mmol), 1-[(5-bromo-2-thienyl)sulfonyl]pyrrolidine (60 mg, 0.17 mmol, 1 eq), PdCl2(dppf)-CH2Cl2 adduct (20 mg, 0.024 mmol, 0.15 eq), and potassium carbonate (100 mg, 0.72 mmol, 4.3 eq) were diluted in a mixture of 1,4-dioxane (3 mL) and water (1.5 mL) in a 2-5 mL microwave tube. The mixture was degassed by bubbling argon through for 5 minutes, then heated in a biotage microwave at 100° C. for 5 minutes. The crude reaction mixture was filtered through a thiol SPE cartridge (polymer labs) to remove palladium, and concentrated. The residue was dissolved in ˜3 mL of dmso, and filtered. The crude product was purified by ammonium hydroxide Gilson hplc, and the desired fractions were evaporated. The product was further purified by trituration from diethyl ether to afford 19.5 mg (21%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of 48.8 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate, 600 mL of THF, and 200 mL of N,N-dimethylformamide (DMF) was added 10.0 g of 10% palladium on carbon (wetted with 55% H2O), followed by stirring at room temperature for 8 hours under a hydrogen atmosphere (1 atm). The inside of the reaction container was replaced with argon, and then the insoluble materials were filtered off on a celite layer. The filtrate was concentrated under reduced pressure, and to the residue was added 1000 mL of water, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration to obtain 43.3 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate as a white solid.