Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1(C)C=CC=CC=1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 6 h

Procedure:
After (S)-1-phenylethyl alcohol (176 mg, 1.43 mmol), triphenylphosphine (449.8 mg, 1.72 mmol), 4-nitrobenzoic acid (288 mg, 1.72 mmol), and toluene (7 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (403 mg, 1.72 mmol) dissolved in toluene (3.5 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 6 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using toluene (10 mL,×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (352 mg, yield: 91%/(S)-1-phenylethyl alcohol).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1[Cl:20].N>>[Cl:20][C:13]1[CH:14]=[C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH:16]=[CH:17][C:12]=1[Cl:11]
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Clc1ccc(-c2cc(-c3cccnc3)no2)cc1Cl

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 86 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dd, J=8.1, 5.0 Hz, 1H), 7.82-8.00 (m, 3H), 8.21 (d, J=2.0 Hz, 1H), 8.38 (dt, J=7.9, 1.8 Hz, 1H), 8.78 (dd, J=4.8, 1.6 Hz, 1H), 9.14 (d, J=1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 291 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:36])[C:24]2[C:16](=[CH:17][C:18]3[NH:19][C:20]([S:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:21][C:22]=3[CH:23]=2)[C:15]([CH3:34])([CH3:33])[C:14]1=[O:35]>C(OCC)(=O)C.C(Cl)Cl>[CH3:12][C:13]1([CH3:36])[C:24]2[C:16](=[CH:17][C:18]3[NH:19][C:20]([S:25]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:9])=[N:21][C:22]=3[CH:23]=2)[C:15]([CH3:34])([CH3:33])[C:14]1=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(SCc4ccccn4)nc3cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S(=O)Cc4ccccn4)nc3cc21
Reaction time: 3 h
Yield: 42.3 %

Procedure:
31 ml of a 10% solution of m-chloroperbenzoic acid in ethyl acetate were added dropwise with intensive stirring at 0°-5° C. to 6.16 g of 5,7-dihydro-5,5,7,7-tetramethyl-2-[(2-pyridylmethyl)thio]indeno(5,6-d)-imidazol-6(1H)-one, dissolved in 100 ml of methylene chloride, in a 250 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and calcium chloride tube. After stirring at 0°-5° C. for 3 hours, the mixture was poured into 1 l of methylene chloride, it was washed twice with 250 ml of 2N soda, then neutral with water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residue from acetonitrile gave 2.7 g (42.3% of theory) of 5,7-dihydro-5,5,7,7-tetramethyl-2-[(2-pyridylmethyl)sulfinyl]indeno(5,6-d)imidazol-6(1H)-one of melting point 201°-203° C.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:1][CH:2]([CH:4]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]2)[CH3:3])=[CH:37][CH:36]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a flask charged with tert-butyl 3-(1-hydroxyethyl)azetidine-1-carboxylate (212 mg, 1.053 mmol) was added THF (6.3 mL), resin bound PPh3 (527 mg, 1.580 mmol), p-chlorophenol (104 μL, 1.053 mmol) and DEAD (250 μL, 1.580 mmol). The reaction mixture was stirred overnight at RT. The reaction mixture was filtered through cotton and dried under reduced pressure, then purified with flash chromatography ramping CH2Cl2:MeOH:NH4OH (90:10:1) in CH2Cl2 from 0% to 100% to afford tert-butyl 3-(1-(4-chlorophenoxy)ethyl)-azetidine-1-carboxylate (145 mg, 44%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][O:16][C:17]1[CH:40]=[CH:39][C:20]([CH2:21][O:22][CH2:23][CH:24]([O:37][NH2:38])[CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][CH2:23][CH:24]([O:37][NH:38][C:2]2[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=2[NH:8][CH:9]=[O:10])[CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(COCCC(COCc2ccc(OC)cc2)ON)cc1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(COCCC(COCc2ccc(OC)cc2)ONc2nc(NC=O)nc(Cl)c2NC=O)cc1

Procedure:
A solution of 4,6-dichloro-2,5-diformamidopyrimidine (3.27 g, 13.9 mmol), 1,4-bis(4-methoxybenzyloxy)but-2-oxyamine (5.06 g, 14 mmol) and triethylamine (5.88 ml, 42 mmol) in dioxan (100 ml) was heated at 100° C. for 90 minutes. The solution was allowed to cool, filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1) to afford 6-[1,4-bis (4-methoxybenzyloxy)but-2-oxyamino]-4-chloro-2,5-diformamidopyrimidine as a pale yellow foam. 1H NMR: δH (CDCl3) 1.88 (2H, m, 3-H), 3.54 (4H, m, 1'-H and 4'-H), 3.73 (3H, s, CH3), 3.74 (3H, s, CH3), 4.07 (1H, m, 2'-H), 4.37 (4H, m, 2×ArCH2), 6.88 (4H, m, ArH), 7.21 (4H, m, ArH), 9.17, 9.27, 9.30, 9.43 (total 2H, 4×s, D2O exchange leaves s at 9.27, 2×HCO), 10.67 (1H, br.s, D2O exchangeable, NH) and 10.85 (1H, br.s, D2O exchangeable, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Sc1ccc(Cl)cc1Cl
Product: Fc1ccc(Sc2ccc(Cl)cc2Cl)c(Br)c1

Procedure:
Prepared from 2,4-dichloro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])([CH:7]([CH3:9])[CH3:8])[CH2:3]1.[OH:28][C:29]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][N:37]=2)[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:7]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:5][CH2:6][C@@H:2]([NH:1][CH:32]2[CH2:31][CH2:30][C:29]([C:36]3[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[CH:44][CH:45]=[CH:46][N:47]=4)=[CH:38][N:37]=3)([OH:28])[CH2:34][CH2:33]2)[CH2:3]1)([CH3:8])[CH3:9]
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1

Procedure:
To a solution of ((1S,3R)-3-amino-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (50 mg, 0.13 mmol) in DCM (2 mL) was added 4-hydroxy-4-(5-(pyrimidin-2-yl)pyridin-2-yl)cyclohexanone (1.5 equiv) and sodium triacetoxyborohydride (1.5 equiv). The mixture was stirred until complete, portioned and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. Chromatography gave the title compound as a white powder after lypholization. MS calculated for C32H42F3N7O2: (M+H) 638; found 638.3.
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:19][C:18]([S:38]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[CH:44][CH:43]=2)(=[O:40])=[O:39])=[CH:17]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1.C(O)(=O)C.[OH-].[Na+:58]>C(O)C>[Na+:58].[Na+:58].[Na+:58].[C:20]1([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O-:34])=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:25])[C:21]2[C:16](=[CH:15][C:14]([S:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([O-:52])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:13])=[CH:23][CH:22]=2)[CH:17]=[C:18]([S:38]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O-:48])=[O:47])=[CH:50][CH:51]=2)(=[O:40])=[O:39])[CH:19]=1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4ccc(C(=O)OC)cc4)cc(S(=O)(=O)Nc4ccc(C(=O)OC)cc4)cc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([O-])c1ccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4ccc(C(=O)[O-])cc4)cc(S(=O)(=O)Nc4ccc(C(=O)[O-])cc4)cc3c2)cc1
Reaction time: 0.75 h

Procedure:
A 9.0 g portion of the product of Example 7 is dissolved in 46.5 ml of 2N sodium hydroxide and stirred for 45 minutes. The solution is neutralized with 2.7 ml of glacial acetic acid and diluted with 200 ml of ethanol. A yellow solid separates which is collected by filtration, washed with ethanol and ether, and dried to give 8.7 g of the product of the Example.
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH:5]1[CH2:8][CH:7]([C:9](O)=[O:10])[CH2:6]1)[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:9]([CH:7]1[CH2:8][CH:5]([CH2:4][CH:3]([CH2:12][CH3:13])[CH2:1][CH3:2])[CH2:6]1)=[O:10]
Reactant: CCC(CC)CC1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)CC1CC(C(=O)N(C)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
3-(2-Ethylbutyl)cyclobutanecarboxylic acid (10.0 g) and chloroform (100 mL) were mixed. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (6.36 g), N,N-diisopropylethylamine (11.3 mL), WSC.HCl (12.5 g) and 4-dimethylaminopyridine (7.96 g) at ice temperature. The mixture was stirred at RT overnight. After an addition of 6 N hydrochloric acid (40 mL) at ice temperature, the aqueous layer was removed. The organic layer was washed with 1 N hydrochloric acid (50 mL), water (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (13.2 g) as a crude product.
Reaction SMILES: Cl.[C:2]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:15]3[C:20]([CH:21]=2)=[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18](=[O:30])[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]>CO.C(OCC)(=O)C.[Pt]=O>[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:15]3[C:20]([CH:21]=2)=[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18](=[O:30])[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CC=C(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCC(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Reaction time: 1 h

Procedure:
A solution of 8-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one hydrochloride (Example 19, 24 mg) in methanol/ethyl acetate=1/5 was added platinum oxide (9 mg). The solution was hydrogenated under hydrogen (1 atm) for 1 h. The mixture was filtered though celite and concentrated. The residue was purified by silica gel (methylene chloride/methanol/2N ammonia=10/1/0.2) to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[N:17]1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1nccc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1nccc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 85.6 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0443 g, 0.188 mmol), 1-methyl-1H-pyrazole-5-carbonyl chloride (0.028 g; 0.188 mmol), and triethylamine (0.066 mL; 0.470 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0487 g (86%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxamide as a solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[O:20][CH:21]=1)C)(C)(C)C.C(OCC)C.Cl>CO>[O:20]1[CH:21]=[C:17]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][NH:7][CH3:6])[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]1=2
Reactant: CN(Cc1ccccc1Sc1coc2ccccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CNCc1ccccc1Sc1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2-(Benzo[b]furan-3-ylsulfanyl)-benzyl]-methyl-carbamic acid tert-butyl ester (9.2 g, 24.9 mmol) is dissolved in methanol (75 mL) and diethyl ether saturated with hydrochloric acid (75 mL) is added. The mixture is stirred at ambient temperature for 1 hour and then concentrated in vacuo. Water (50 mL) is added to the remanence and the mixture is basified by addition of aqueous ammonia (conc.). The aqueous fraction is extracted with ethyl acetate (3×100 mL). The combined organic fractions are dried (MgSO4) and concentrated in vacuo. The product is purified by preparative HPLC or by silica gel chromatography eluting with ethyl acetate-triethyl amine (25:1) to furnish the title compound as an oil. This oil can be redissolved in ethyl acetate (75 mL). Diethyl ether saturated with hydrochloric acid can be added hereto until pH 2. The precipitated material can then be filtered off and dried in vacuo to give 6.9 g (91%) of [2-(benzo[b]furan-3-ylsulfanyl)-benzyl]-methyl-amine hydrochloride as a white crystalline material.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Br:7])[N:6]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Br:7])[N:6]=1
Reactant: O=Cc1sc(Br)nc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
2,4-Dibromo-thiazole-5-carbaldehyde (2.0 g, 7.4 mmol) in methanol (80 mL) was treated with NaBH4 (419 mg, 11.0 mmol). The reaction mixture was stirred at rt overnight, quenched with 10% NaOH, diluted with water and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (3:1) to give the title compound (1.84 g, 91%). MS (DCI/NH3) m/z 274 (M)+. 1HNMR (500 MHz, CDCl3) δ ppm 2.11 (s, 1H) 4.78 (s, 2H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.Cl.[CH2:44]([O:51][NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:13]([O:20][N:21]([C:22](=[O:28])[CH2:23][CH2:24][C:25](=[O:27])[NH:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][NH:52][O:51][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCCCCNOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (CDI, 0.592 g, 3.65 mmol) was added to (8) (1.42 g, 3.48 mmol) in dry CH2Cl2 (90 mL) . After stirring for 1 hour, the solution was cooled to 0° C. and (6) (free amine, 0.74 g, 3.55 mmol) in CH2Cl2 (65 mL) was added by cannula over 5 minutes. After stirring for 12 hours (0° C. to room temperature), solvent was removed by rotary evaporation. Dilute brine (200 mL) was added, followed by extraction with EtOAc (4×100 mL). The organic phase was washed with 100 mL portions of cold 0.5M citric acid, 5% NaHCO3 and brine. Solvent removal led to 2.2 g (quantitative) of (9) as an oil, which was used directly in the next step. An analytical sample was chromatographed on silica gel, eluting with 3.5% EtOH/CHCl3 : 300 MHz NMR δ 1.1-1.7 (m+s, 21 H), 2.3-3.3 (m, 10 H), 3.60 (t, 2 H, J=7), 4.6 (br s, 1 H), 4.67 (s, 2 H), 4.80 (s, 2 H), 6.0 (br s, 1 H), 7.25-7.40 (m, 10 H). Anal. calcd. for C33H50N4O6 : C, 66.19; H, 8.42; N, 9.36. Found: C, 66.27; H, 8.40; N, 9.33.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][NH2:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][NH:31][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:23])=[O:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2S(C)(=O)=O)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1Cl
Product: Cc1ccc(CNC(=O)c2nc(-c3ccc(F)cc3S(C)(=O)=O)n(C)c(=O)c2O)cc1Cl

Procedure:
Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 3-chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (58.6 mg, 81% yield). 1HNMR (500 MHz, CDCl3) δ: 12.12 (1H, s), 7.87 (1H, dd, J=7.63, 2.45 Hz), 7.53 (1H, t, J=5.50 Hz), 7.48 (1H, td, J=7.62, 2.74 Hz), 7.42 (1H, dd, J=8.24, 4.89 Hz), 7.20 (1H, s), 7.17 (1H, d, J=7.63 Hz), 7.05 (1H, d, J=7.63 Hz), 4.57 (1H, dd, J=14.95, 6.72 Hz), 4.43 (1H, dd, J=14.95, 5.49 Hz), 3.26 (3H, s), 3.05 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C21H20ClFN3O5S (M+H): 480.0796; found: 480.0793.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=C(C=O)[N:12]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[C:10]=1[O:21][CH3:22])=O)(C)(C)C.COCCN(S(F)(F)F)CCOC.[C:43](O)([C:45]([F:48])(F)[F:46])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:43]([CH:45]([F:48])[F:46])[N:12]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[C:10]=1[O:21][CH3:22]
Reactant: COC(=O)c1nc(C=O)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1OC
Reactant: O=C(O)C(F)(F)F
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(C(F)F)cc(N)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a 0° C. solution of methyl 4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate (0.279 g, 0.680 mmol) in CH2Cl2 (2.72 ml) was added DEOXO-FLUOR® (0.251 ml, 1.360 mmol). The mixture was stirred at 0° C. for 1 h (reaction completed based on TLC and LC). TFA (1 mL) was then added and the reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The mixture was poured into saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (ISCO, SiO2 12 g, hexanes/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-6-(difluoromethyl)-3-methoxypicolinate (89 mg, 0.383 mmol, 56.4% yield) as a white solid. ESIMS m/z 233 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.54 (t, J=55.4 Hz, 1H), 4.69 (s, 2H), 3.98 (s, 3H), 3.90 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −114.65.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)=[O:2].CO>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12
Reactant: CC1(C)CCc2c(C(=O)O)sc(C=O)c2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCc2c(C(=O)O)sc(CO)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To a solution of crude 3-formyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.38 g, 10 mmol) in methanol (20 mL) NaBH4 (756 mg, 20 mmol) is added in portions. The mixture is stirred at rt for 15 min, diluted with 10% aq. citric acid and brine and extracted with TBME. The organic extract is dried over Na2SO4 and the solvent is removed under reduced pressure to give 3-hydroxymethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.30 g) as a beige foam; LC-MS: tR=0.83 min, [M+1]=241.22; 1H NMR (CDCl3): δ 4.69 (s, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.32 (s, 2H), 1.50 8 t, J=7.0 Hz, 2H), 0.94 (s, 6H).
Reaction SMILES: [CH:1]1([C@H:4]([O:6][C:7](=[O:31])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.O>CN(C=O)C>[CH:1]1([C@H:4]([O:6][C:7](=[O:31])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:28][CH2:29][CH2:30]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of (R)-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.083 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.046 g, 0.4 mmol) in DMF (2.0 mL) was stirred at 70° C. for 2 h. After cooling to room temperature, the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water, purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester (0.073 g, 74%).