Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:26])=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:18]([OH:25])=[CH:17][CH:16]=2)[N:10]=1.[CH2:27]([N:29]([CH2:32][CH2:33][O:34][CH2:35][CH2:36]Cl)[CH2:30][CH3:31])[CH3:28].[Cl-].[OH-].[Na+]>CN(C)C=O>[CH3:3][C:4]1[NH:5][C:6]([CH3:26])=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:18]([O:25][CH2:36][CH2:35][O:34][CH2:33][CH2:32][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:17][CH:16]=2)[N:10]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(O)c4c3CCCC4)n2)c(C)[nH]1
Reactant: CCN(CC)CCOCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOCCOc1ccc(-c2cccc(-c3cc(C)[nH]c3C)n2)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a three-necked 125 mL round-bottomed flask equipped with nitrogen (N2) inlet and septum were added 15 mL dry dimethylformamide and 50 mg (1.3 mmol) sodium hydride (washed with hexane). The reaction was cooled to 0° C., and a solution of 200 mg (0.6 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine in 5 mL dry dimethylformamide added dropwise. The reaction was stirred 30 min at room temperature, then a solution of 234 mg (1.3 mmol) diethylaminoethoxy-ethyl chloride (J. Med. Chem., 34, 3159 (1991)) in 5 mL dry dimethylformamide added dropwise and the reaction heated at 100° C. for 20 hour, followed by more sodium hydride and chloride and heating another 24 hour The reaction was cooled, poured into aqueous sodium hydroxide solution, and extracted into ethyl acetate. The organic layer was washed with water, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 83 mg (30%) of an oil. 1H-NMR (δ, CDCl3): 1.03 (t, J=7, 6H), 1.67 (m, 2H), 1.76 (m, 2H), 2.155 (s, 6H), 2.59 (q, J=7, 4H), 2.7-2.9 (m, 6H), 3.67 (t, J=7, 2H), 3.84 (t, J=6, 2H), 4.14 (t, J=6, 2H), 5.87 (s, 2H), 6.73 (d, J=8, 1H), 7.11 (d, J=8, 1H), 7.185 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.82 (t, J=8, 1H); 13C-NMR (δ, CDCl3): 11.68, 13.33, 22.30, 22.87, 23.68, 28.66, 47.61, 52.34, 67.65, 69.67, 70.10, 106.52, 107.80, 119.48, 122.95, 126.59, 127.68, 128.62, 132.55, 136.58, 137.84, 151.21, 156.85, 160.34; MS (%): 462 (parent+1, 100).
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[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[S:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:26]2[CH2:27][CH2:28][S:24][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CSCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCSC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) and thiazolidine (0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (68 mg, 28%) which was obtained as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[N:5]=[C:6]([NH:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:16][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[S:7][C:6]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[N:5][C:4]=2[CH3:3])=[CH:10][CH:11]=1)=[O:1]
Reactant: OO
Reactant: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(C)=O)cc1
Yield: 32.4 %

Procedure:
Hydrogen peroxide solution (27% in water) (35 ml, 0.28 mmol) is added to a stirred suspension of [4-methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (27c) (0.090 g, 0.28 mmol) in acetic acid (5 ml). After 30 minutes the reaction is diluted with water and brought to pH 10 by addition of aqueous sodium hydroxide. The product is extracted with ethyl acetate (3×50 ml), the combined organic extracts are washed with brine (50 ml), dried (MgSO4) and the solvent removed to give the title compound as an orange solid (0.03 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:7]1=[CH:8][C:9]3[CH2:10][C:11]4[CH:12]=[CH:13][C:14]([Br:21])=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:26])[CH3:25].[BH4-].[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:7]1=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:26])[CH3:25])[CH:15]=[C:14]([Br:21])[CH:13]=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1cc(Br)ccc1C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)c2cc(Br)ccc2-c2cc3cc4ccc(Br)cc4cc3cc21
Temperature: 100 °C
Yield: 69.6 %

Procedure:
2,9-Dibromo-13,13-dimethyl-6H-indeno[1,2-b]anthracen-11(13H)-one (13 g, 1 eq, 0.027 mol) was placed in a flask, and IPA (200 ml) was added thereto. Then, sodium borohydride (3.1 g, 3 eq, 0.081 mol) was gradually added at 0° C., the reaction mixture was stirred at 100° C. while heating for 24-36 hours and cooled to room temperature, and ice water was gradually added thereto. The resultant solid was filtered, several times washed with distilled water, dried and purified by column chromatography to give 2,9-dibromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (EMI 11) (8.5 g, yield=70%).
Reaction SMILES: C(OC(=O)[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:9]=1)(C)C.[ClH:24]>CO>[ClH:24].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)NCc1cccc(NCCN2CCOCC2)c1
Agent: Cl
Solvent: CO
Product: NCc1cccc(NCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [3-(2-morpholin-4-yl-ethylamino)-benzyl]-carbamic acid isopropyl ester (200 mg, 0.596 mmol), methanol (4 mL) and 4.89N isopropanolic hydrochloric acid (2.4 mL) was stirred at room temperature overnight. The reaction was concentrated and dried to yield (3-aminomethyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine hydrochloride (212 mg) as an orange solid. m/z (M+1) 236.04.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1.O>CO>[CH:3]1([CH2:8][CH2:9][CH2:10][CH:11]([OH:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)CCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)CCCC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
NaBH4 (3.15 g; 83 mmol) was added portionwise to a solution of 5-cyclopentylpentan-2-one (16.0 g; 104 mmol) in MeOH (125 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. Water (100 ml) was added cautiously and the mixture extracted with MTBE (3×250 ml). The organic phases were combined, washed with brine (3×50 ml), dried over MgSO4, concentrated in vacuo and distilled (52° C.-56° C./0.045 torr) to give 14.5 g (90% yield) of 5-cyclopentylpentan-2-ol.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:28][CH:27]=1)#[N:25].CCCCCC.CCCCCC.C(Cl)Cl>COC(C)(C)C.O1CCCC1.C(Cl)Cl>[CH3:2][O:3][CH:4]=[C:37]1[CH2:38][CH2:39][CH:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH2:35][CH2:36]1
Reactant: N#Cc1ccc(CCC2CCC(=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COC=C1CCC(CCc2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A suspension of 54.4 g of methoxymethyl-triphenylphosphonium chloride in 315 ml of t-butyl methyl ether was treated with 18.8 g of potassium t-butylate while gassing with argon at -10° C. and the orange suspension was stirred for a further 30 minutes at 0° C. The mixture was subsequently treated dropwise within 30 minutes at 0° C. with a solution of 25.1 g of 4-[2-(p-cyanophenyl)ethyl]cyclohexanone in 260 ml of tetrahydrofuran and the mixture was stirred for a further 3 hours at room temperature. Thereafter, the reaction mixture was poured into 2.6 l of hexane, stirred for 10 minutes and suction filtered (rinsing with hexane). The filtrate was concentrated in vacuo at 50° C., whereby 47.7 g of yellow, partially crystalline residue were obtained. Low-pressure chromatography (0.3 bar) of the residue on silica gel with hexane/methylene chloride (vol. 4:1) and methylene chloride gave 21.0 g of p-[2-(4-methoxymethylenecyclohexyl)ethyl]benzonitrile as a yellowish oil; Rf-value (methylene chloride) 0.43.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (280 mg, 1.71 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (491 mg, 2.56 mmol) and 1-hydroxy-1H-benzotriazole (261 mg, 1.71 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (523 mg, 75%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[O:7]=[C:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[C:3](=[O:12])[N:2]1[O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A mixture of N-hydroxyphthalimide (10 g, 61.3 mmol), K2CO3 (16.9 g, 122 mmol) and tert-butyl bromoacetate (12 g, 9 mL, 61.3 mmol) in DMF (60 mL) was stirred at room temperature for 3 hours and the solvent was evaporated under high vacuum. The residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was recrystallized from a mixture of CH2Cl2/EtOAc/hexane to give the title compound (12 g, 71% yield) as a white solid. Mp 140-141° C. 1H NMR (300 MHz, CDCl3) δ 7.80-7.90 (m, 2H), 7.74-7.77 (m, 2H), 4.71 (s, 2H), 1.49 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 166.0, 163.0, 134.7, 128.9, 123.7, 83.0, 73.5, 28.1. Mass spectrum (API-TIS) m/z 278 (MH+), 295 (MNH4+). Anal. calcd. for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.47; H, 5.31; N, 4.96.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: OB(O)c1ccccc1O
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2 g, 5.95 mmol) obtained in the same manner as in the method described in WO03/010140 and 2-hydroxyphenylboronic acid (1.23 g, 8.91 mmol) in 1,2-dimethoxyethane (20 ml) and water (10 ml) were added lithium chloride (504 mg, 11.9 mmol), sodium carbonate (1.9 g, 17.9 mmol) and tetrakis(triphenylphosphine)palladium (687 mg, 0.59 mmol), and the mixture was heated under reflux for 10 hr. The mixture was allowed to cool to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (1.81 g, yield 87.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1(O)[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH:4]=[C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 81.3 %

Procedure:
A solution of (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester (1.28 g, 3.42 mmol) and para-toluenesulfonic acid (0.50 g) in 250 mL of benzene was refluxed for 2 hours using a Dean-Stark trap. The reaction mixture was cooled and poured into 500 mL of EtOAc, and this organic phase was washed with water, saturated NaHCO3, and dried (MgSO4). Evaporation under reduced pressure gave a dark oil that was purified by elution on silica gel (hexanes:EtOAc 7:3) to yield 0.991 g (2.78 mmol, 81.2% of a white crystalline solid. MS: 357 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[CH:38][C:37]([CH3:40])=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[CH:38][C:37]([CH3:40])=[N:36]1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)benzoic acid. MS (ESI) 327 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:26])[NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1cccnc1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CC1(C)CN(CC(=O)Nc2cccnc2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 55 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 3-aminopyridine. The product was isolated as hydrochloride salt in 55% yield. 1HNMR (300 MHz, D2O): δ 1.34 (s, 3H), 1.54 (s, 3H), 2.60 (d,1H), 3.4 (d, 1H), 3.50 (d, 1H), 3.70 (t, 1H), 3.81 (d, 1H) 4.23 (d, 2H), 7.69 (d, 1H), 7.98 (d, 1H), 8.01 (d, 1H), 8.17(d, 1H), 8.42 (d, 1H), 8.48-8.55 (m, 3H), 9.09 (s,1H), 9.30 (d, 1H). Retention Time (LC, method: ammonium acetate standard): 1.56 min. MS (M+H+): 493.2.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:33].C(OCC)(=O)C>>[ClH:33].[ClH:33].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl{trans-2-[4-({[3-(piperidin-1-yl)phenyl]carbonyl}amino)phenyl]cyclopropyl}carbamate (142 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give the title compound (121 mg).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(N)C=1OC[C:47]([F:50])([F:49])[F:48]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][C:47]([F:50])([F:49])[F:48])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: Nc1ncnc(Cl)c1OCC(F)(F)F
Product: Nc1ncnc(N2CCC(c3nc(-c4ccnc(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1OCC(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine using 6-chloro-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine instead of 6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=571, obsd.=571).
Reaction SMILES: O=[C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O.[CH2:23]([NH2:26])[CH2:24][NH2:25]>O1CCOCC1>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:2]23[NH:26][CH2:23][CH2:24][N:25]2[C:9](=[O:11])[C:5]2[N:4]([CH:8]=[CH:7][CH:6]=2)[CH2:3]3)=[N:14][CH:15]=1
Reactant: NCCN
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cn1
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3ccc(C(F)(F)F)cn3)NCCN12
Reaction time: 96 h
Yield: 83.5 %

Procedure:
To a solution of methyl 1-{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H-pyrrole-2-carboxylate (85 mg, 0.26 mmol) in 1,4-dioxane (20 mL) was added ethane-1,2-diamine (0.65 mL, 9.7 mmol). The solution was heated at reflux. After 4 days the reaction was complete (monitored by LCMS). The mixture was then concentrated in vacuo to give an oily solid. The material was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient CH2Cl2 1 CV, 0-10% MeOH in CH2Cl2 10 CV) to give 10a-[5-(trifluoromethyl)pyridin-2-yl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (70 mg, yield: 85%). ESI-MI m/z [M+H]+ 323.0.
Reaction SMILES: N[C:2]1N=C(N2CCC3(CN[C@H](C(OC(C)C)=O)C3)CC2)C=C(O[C@H](C2C=CC(C3C=CC(C)=C(C)C=3)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1.[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([OH:67])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][C:77]=2[C:83]2[CH:88]=[CH:87][CH:86]=[C:85]([S:89](=[O:92])(=[O:91])[NH2:90])[CH:84]=2)[C:72]([F:75])([F:74])[F:73])[N:52]=1>>[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:58][CH2:59][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([O:67][CH3:2])=[O:66])[CH2:61]3)[CH2:68][CH2:69]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][C:77]=2[C:83]2[CH:88]=[CH:87][CH:86]=[C:85]([S:89](=[O:91])(=[O:92])[NH2:90])[CH:84]=2)[C:72]([F:75])([F:74])[F:73])[N:52]=1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2cccc(S(N)(=O)=O)c2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Product: COC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4cccc(S(N)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]#[C:16][Si](C)(C)C)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CO>[C:15]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([OH:1])[CH:3]=1)[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13])#[CH:16]
Reactant: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(O)c2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 2.2 g, 7.4 mmol) in methanol (20 mL) was treated with potassium carbonate (2.04 g, 14.8 mmol) and the resulting reaction mixture was stirred at ambient temperature for 5 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as an oil (1.58 g, ˜100%).