Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8]C)[CH:5]=[CH:6][CH:7]=1.Br[CH:11]([CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O>>[CH3:24][C:11]1[S:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=2[C:12]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(S)c1
Product: Cc1sc2cc(O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to examples 26.1–26.3, 3-Mercaptoanisole and 2-Bromo-1-(4-trifluoromethyl-phenyl)-propan-1-one were converted to yield 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol as colorless amorphous solid, MS: 308 (M).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:8]2[N:9]=[CH:10][C:11](Br)=[CH:12][N:7]2[N:6]=1)=[O:4].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:8]2[N:9]=[CH:10][C:11]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][N:7]2[N:6]=1)=[O:4]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cc2ncc(Br)cn2n1
Product: COC(=O)c1cc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, grey solid, MS: m/e=278.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (example 28, step 1) and phenylacetylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16](=[O:27])[CH2:15]1)=[O:12].[BH4-].[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C>CCO.C1COCC1.CCOC(C)=O.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:22][N:19]1[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]([O:27][C:30](=[O:32])[CH3:31])=[CH:15][CH:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:20]1=[O:21]
Reactant: CN1C(=O)C(NC(=O)CCc2ccc(Cl)cc2Cl)CC(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)OC1=CC(NC(=O)CCc2ccc(Cl)cc2Cl)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a stirred suspension of 3-(2,4-Dichloro-phenyl)-N-(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-propionamide (3.7 mmol, 1.5 g) in 15 ml EtOH and 5 ml THF was added NaBH4 (3.7 mmol, 0.14 g). This was stirred at rt for 1 h. The reaction was then diluted with 200 ml EtOAc and extracted with 2×100 ml 1N HCl. The organic layer was dried with brine and evaporated under vacuum to 1.4 g of a white powder. The solid was carried on without further purification. To a stirred suspension of the above alcohol in 4 ml CH2Cl2 was added acetic anhydride (0.73 mmol, 75 mg, 0.07 ml), triethyl amine (0.73 mmol, 74 mg, 0.10 ml), 4-dimethylaminopyridine (0.098 mmol,11.9 mg) and the reaction was stirred at rt. The reaction mixture was then diluted with 25 ml CH2Cl2 and extracted with 25 ml H2O, 25 ml saturated NaHCO3. The organic phase was dried with brine and evaporated to a colorless oil. The resulting oil was chromatographed over silica, eluting with 20% to 50% EtOAc:Hex. The pure fractions were collected, evaporated under vacuum, taken up in CH2Cl2 and allowed to evaporate to dryness overnight, resulting in 110 mg of a white solid. mp 142°-144° C.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]([NH:19][C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C(O)(=O)C>[CH2:21]([C:20]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[CH:17][N:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CNC(=O)Cc1ccccc1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: c1ccc(Cc2ncnn2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
Phenylhydrazine hydrochloride (0.09 g, 0.6 mmol) in 5 mL glacial acetic acid was treated with triethylamine (0.06 g, 0.6 mmol), warmed to 70° C., treated with N-formylphenylacetamide (0.1 g, 0.6 mmol), and heated at 90° C. for 1 hour. The mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organics were washed with saturated NaHCO3, 1M NaOH, water, and brine. The organics were then dried (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40% hexanes/ethyl acetate) to provide the title compound. MS (ESI) m/e: 236 (M+H)+; 1H NMR (DMSO-d6) δ 4.2 (s, 2H), 7.05-7.1 (d, 2H), 7.17-7.3 (m, 3H), 7.45-7.6 (m, 5H), 8.1 (s, 1H); Anal. calcd. for C, 76.57; H, 5.57; N, 17.86. Found C, 76.32; H: 5.81; N, 17.63.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:46][C:44]1[S:45][C:41]2[C:40]([CH:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=2[N:43]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12

Procedure:
From 2-bromo-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 450 (M{81Br}+H+, 100), 448 (M{79Br}+H+, 85).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc2cccnc12
Product: COc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 56.5 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (220 mg, 2 mmol) and 4-methoxy-2-nitrobenzene-1-sulfonyl chloride (420 mg, 2 mmol) gave the title compound (406 mg, 74%) after purification by column chromatography with heptane/EtOAc (50:50-0:100) gradient elution.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]([F:22])([F:21])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:17]([F:22])[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1ccc(C(F)(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(F)(F)F)c(OC(F)F)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A suspension of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (see WO 2007/129745) (2.00 g), sodium chlorodifluoroacetate (2.08 g) and potassium carbonate (2.51 g) in N,N-dimethylformamide (30.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water three times and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-85:15) to give methyl 3-(difluoromethoxy)-4-(trifluoromethyl)benzoate as a colorless oil (1.96 g).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:1][CH:2]([OH:4])[CH3:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)O)cc1
Reaction time: 72 h

Procedure:
In 200 ml of methylene chloride were dissolved 38 g of 1,2-propanediol and 44 g of pyridine and, then, 95 g of p-toluenesulfonyl chloride was added gradually over a period of 15 minutes. The reaction was further conducted at room temperature for 72 hours. The reaction mixture was washed twice with one volume of water each, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was crystallized from toluene-hexane (100 ml-100 ml), filtered, and dried in vacuo to give colorless crystals of (RS)-1-p-toluenesulfonyloxy-2-propanol 2a ##STR21## (54 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]1[O:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[CH2:8]1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:15]([CH2:2][C:3]([NH:5][CH2:6][CH:7]1[O:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[CH2:8]1)=[O:4])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)NCC1CN2C(=O)CC2O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)NCC1CN2C(=O)CC2O1
Yield: 89 %

Procedure:
(3RS,5RS)-3-(N-Chloroacetylaminomethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one(500 mg), of example 8, and Sodium azide(297 mg) were stirred in Dimethyl sulfoxide(10 ml) at room temperature for 14 hrs. The reaction mixture was diluted with Ethyl acetate, washed with water, brine and dried over Magnesium sulfate. The residue, which obtained after removal of solvent in vacuo, was purified by silicagel column chromatography (Hexane+Ethyl acetate 1:2). The title compound was obtained as oil.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (3.9 g) in anhydrous tetrahydrofuran (60 mL) at 0° C. was treated with a mixture of tert-butanol (0.15 mL) and 3-oxopentanoic acid ethyl ester (5.0 g). The mixture was warmed to room temperature and after 30 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (8.6 g) in tetrahydrofuran (20 mL) was added and the resulting mixture heated at 70° C. for 17 hours. The mixture was cooled to room temperature and diluted with water (20 mL) and this mixture was extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified, by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford title compound as a white solid, 3.6 g.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.CN(P(N(C)C)(N(C)C)=O)C.[CH2:35](Br)[CH:36]=[CH2:37]>C1COCC1>[CH2:37]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:19]1=[O:23])[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1CCc2cc(OC)ccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of LiHMDS (1.04 g, 6.24 mmol), in THF (40 mL) cooled at −78° C. is added slowly a solution of 6-methoxy-1-tetralone (1.0 g, 5.67 mmol) in anhydrous THF (40 mL). After the addition is complete, the solution is stirred at −78° C. for 30 minutes, then HMPA (1.97 mL, 11.3 mmol) is slowly added and the mixture is stirred for other 5 minutes followed by the addition of a solution of allyl bromide (0.74 mL, 8.5 mmol) in anhydrous THF (5 mL). The mixture is left to warm slowly to room temperature (2-3 h) and quenched at 0° C. with aqueous 1N HCl (20 mL), then extracted with diethylether. The organic phase is dried over MgSO4 and concentrated to dryness. The residue is purified by column chromatography on SiO2 (Petroleum Ether/EtOAc=95:5) to afford the title compound 53 as a colorless oil (Yield 0.56 g, 45%).
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([O:17][CH3:18])[CH:13]=[C:12]1[CH2:19][CH2:20][CH2:21][CH2:22][C:11]=21)([O:5][CH2:6][CH3:7])=[O:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([N:9]1[C:10]2[C:15](=[C:14]([O:17][CH3:18])[CH:13]=[C:12]3[CH2:19][CH2:20][CH2:21][CH2:22][C:11]3=2)[CH:16]=[C:8]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(OC)cc3c(c2[nH]1)CCCC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(OC)cc3c(c2n1Cc1ccccc1)CCCC3
Reaction time: 18 h
Yield: 37.4 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (4.08 g, 0.102 mol) was washed once with hexane and suspended in dry N,N-dimethylformamide (100 mL). 2-Carboethoxy-4-methoxy-6,7,8,9-tetrahydro-1H-benz[g]indole (25.4 g, 92.7 mmol) was added in several portions resulting in gas evolution. Benzyl bromide (12.1 mL, 102 mmol) was added in two portions over 30 min and the resulting mixture stirred for 18 h. Additional portions of 60% sodium hydride suspension (1.30 g) and benzyl bromide (2 mL) were added and the mixture stirred for 27 h. The mixture was poured into water (2 L) and the resulting solution extracted three times with ethyl acetate. The combined extracts were Washed three times with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel) provided 12.6 g (37%) of the title compound as a yellow solid: mp 86-88° C. 1H NMR (CDCl3) δ 7.51 (s, 1H), 7.20 (m, 3H), 6.84 (d, J=6.6 Hz, 2H), 6.24 (s, 1H), 6.12 (s, 2H), 4.23 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.96 (m, 2H), 2.85 (m, 2H), 1.71 (m, 4H), 1.30 (t, J=7.0 Hz, 3H); MS ES+ m/e 364 (p+1); IR (CHCl3, cm−1) 2937, 1701, 1502.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1>[C:21]1([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of carbazole (0.34 g, 2.0 mmol) in xylene (4 ml) were added sodium tert-butoxide (0.23 g, 2.4 mmol), bromobenzene (0.23 ml, 2.2 mmol), palladium acetate (4.5 mg, 0.02 mmol) and 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.1 mg, 0.04 mmol) obtained in Example 4 under a nitrogen atmosphere and the mixture was stirred for 3 hours at 120° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give N-phenylcarbazole (0.479 g, 98%, purity: >99%) as white crystal.
Reaction SMILES: C([NH:11][CH:12]([CH3:24])[CH2:13][O:14][CH:15]1[CH:19]([CH3:20])[CH2:18][CH:17](C)[C:16]1([CH3:23])[CH3:22])(OCC1C=CC=CC=1)=O.[CH3:25]O>[Pd]>[NH2:11][CH:12]([CH3:24])[CH2:13][O:14][CH:15]1[C:16]([CH3:22])([CH3:23])[CH2:17][CH2:18][C:19]1([CH3:20])[CH3:25]
Reactant: CO
Reactant: CC(COC1C(C)CC(C)C1(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(N)COC1C(C)(C)CCC1(C)C

Procedure:
N-Cbz-1-(2-Aminopropoxy)-2,2,3,5-tetramethylcyclopentane is dissolved in CH3OH and hydrogenated over 5% Pd/C in a Parr hydrogenation apparatus. When the reaction is complete the mixture is filtered through Celite and concentrated to yield 1-(2-amino-propoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH:32]=O)[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH2:32][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=4[N:10]=[C:9]3[C:18]([OH:21])([CH3:19])[CH3:20])[CH2:6][CH2:7]1)[CH2:26]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCC(N)CC1
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of 2-[1-(4-amino-cyclohexyl)-5-methyl-1H-benzoimidazol-2-yl]-propan-2-ol (prepared as cis/trans-isomer mixture) and 5-chloro-indan-2-carbaldehyde. The less polar of the two substances isolated by chromatography gave cis-2-(1-{4-[(5-chloro-indan-2-ylmethyl)-amino]-cyclohexyl}-5-methyl-1H-benzoimidazol-2-yl)-propan-2-ol. The analysis of the 1H-NMR confirmed the cis-conformation of the cyclohexane. LC-MS showed a single peak, C27H34ClN3O (m/e) calcd 451.2390, obsd 452.3 (M+H). 1H-NMR (CD3OD) □ 7.83 (d, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 7.03 (d, 1H), 5.32 (m, 1H), 3.16 (m, 2H), 2.96 (br s, 1H), 2.73-2.85 (m, 7H), 2.43 (s, 3H), 2.00 (m, 2H), 1.72 (s, 6H), 1.68 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1cccc2[nH]ncc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3cccc4[nH]ncc34)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
4-bromo-1H-indazole (37.9 mg, 0.192 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (145.7 mg, 0.384 mmol), Fibercat palladium catalyst (Johnson-Matthey, 64.7 mg), and K2CO3 (2 M in water, 0.75 ml, 1.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (2.3 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, washed with water (3×5 ml), dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->75% EtOAc/hexanes). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (7.4 mg, 10%). MS (ESI pos. ion) m/z: 370 (M+H). Calc'd Exact Mass for C22H15N3OS: 369.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][C:36](=[O:43])[N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:33])[CH:27]=1.Cl>O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]1[CH2:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[C:32]([O:34][CH2:35][C:36](=[O:43])[N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCC(=O)N3CCCCC3)c1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCC(=O)N1CCCCC1)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-Butyl 4-oxo-3-(3-((2-oxo-2-(piperidin-1-yl)ethoxy)carbonyl)benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.17 g, 0.29 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-oxo-2-(piperidin-1-yl)ethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(CCCCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>ClCCl.O1CCCC1>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OCCCCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.9 %

Procedure:
To the phenol resin (100 mg), 4-phenylbutan-1-ol (0.42 mmol) was added at room temperature, followed by the addition of dry tetrahydrofuran (0.4 mL) and dichloromethane (0.4 mL). At room temperature, tri-n-butylphosphine (0.42 mmol) was added dropwise thereto and further 1,1′-azobis(N,N-dimethylformamide) (0.42 mmol) was added. The mixture was shaken at room temperature for 5 hours. The resin was taken up by filtration, washed with a mixed solvent (dichloromethane:tetrahydrofuran=1:1) 4 times and dichloromethane 2 times and then dried to give a phenyl ether resin (about 100 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50](=[O:55])[CH2:51][C:52](O)=[O:53].C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C(Cl)CCl>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:52](=[O:53])[CH2:51][C:50]([NH:49][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[O:42][CH3:41])=[O:55])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)CCCOc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCCN(C)C)nc4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of aniline 380 (0.31 g, 0.71 mmol) and DIPEA (0.7 ml, 0.4 g, 3 mmol) in dry DMF (5 mL) was added acid 27 (0.30 g, 1.4 mmol), HOBt (0.040 g, 0.30 mmol), and EDC×HCl (0.40 g, 2.1 mmol) and the mixture was stirred at r.t. for 18 h. Additional EDC×HCl (0.050 g, 0.26 mmol) was added, and the mixture was stirred for a further 6 h. It was then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, dried (anhydrous MgSO4), filtered, and concentrated. Flash chromatography (chloroform/NH4OH) of the residue followed by re-crystallization (90% ethyl acetate/methanol) provided 378 (0.15 g, 32% yield) as a colorless solid. 1H NMR (400 MHz. DMSO-d6) δ (ppm): 10.58 (br s, 1H); 9.63 (br s, 1H); 8.68 (dd, J=2.7, 0.8, 1H); 8.48 (d, J=5.5, 1H); 8.20 (dd, J=8.6, 2.7, 1H); 8.05 (d, J=7.6, 1H); 8.03 (s, 1H); 7.86 (dd, J=13.1, 2.3, 1H); 7.49 (t, J=8.8, 1H); 7.42 (dd, J=8.8, 1.4, 1H); 7.09-7.03 (m, 2H); 6.94 (dd, J=8.8, 0.7, 1H); 6.92-6.88 (m, 1H); 6.61 (dd, J=5.5, 1.0, 1H); 4.33 (t, J=6.7, 2H); 3.85 (s, 3H); 3.63 (s, 2H); 2.33 (t, J=7.2, 2H); 2.13 (s, 6H); 1.84 (quint, J=7.2, 2H). LRMS (M+H): 630.2.