Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)[CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([C:15]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[CH2:12][CH2:13][O:14]1)[CH3:17]
Reactant: CCOC(=O)CC(=O)CC
Reactant: OCCc1csc(-c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(CC)OCCc2nc(-c3ccccc3)sc21
Reaction time: 17 h

Procedure:
A mixture of the starting material of formula II, 2-phenyl-4-(β-hydroxyethyl)thiazole (30.8 g, 0.15 mole, described in Example 1), ethyl propionylacetate (28.8 g, 0.2 mole) and p-toluene-sulfonic acid hydrate (0.25 mole) in toluene (1200 ml) is heated at reflux temperature, with water separation, for 17 hr. Additional ethyl propionylacetate (6 g) and p-toluenesulfonic acid hydrate is added and refluxing is continued for 24 hr. The mixture is evaporated under reduced pressure and the residue is triturated with petroleum ether. The residue is dissolved in a mixture of aqueous sodium bicarbonate solution and ether. The organic solution is separated, dried over sodium sulfate and evaporated under reduced pressure to give ethyl 6,7-dihydro-4-ethyl-2-phenyl-4H-pyrano[4,3-d]thiazole-4- acetate (IV, R1 = H, R2 = CH2CH3, A= COOCH2CH3 and n= 1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[CH2:7][CH2:6]1)=[O:4])[C:25](=[O:30])[CH2:24]2
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)Cc4cc(Cl)ccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-chloro-1,3-dihydro-indol-2-one (116 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL N-methylpyrrolidinone (NMP). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-indol-2-one (2): HPLC retention time, 2.47 minutes, (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 434.3, found, 434.4.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[C:6]([CH3:12])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)=O.[CH:14]1([CH:17]([CH:25]2[CH2:27][CH2:26]2)[N:18]([CH2:22][CH2:23][CH3:24])[C:19]([NH2:21])=[S:20])[CH2:16][CH2:15]1.NC(N)=S>>[CH3:11][C:8]1[CH:7]=[C:6]([CH3:12])[C:5]([C:3]2[N:21]=[C:19]([N:18]([CH:17]([CH:25]3[CH2:27][CH2:26]3)[CH:14]3[CH2:15][CH2:16]3)[CH2:22][CH2:23][CH3:24])[S:20][C:2]=2[CH3:13])=[CH:10][N:9]=1
Reactant: Cc1cc(C)c(C(=O)C(C)Br)cn1
Reactant: CCCN(C(N)=S)C(C1CC1)C1CC1
Agent: NC(N)=S
Product: CCCN(c1nc(-c2cnc(C)cc2C)c(C)s1)C(C1CC1)C1CC1

Procedure:
This compound was prepared according to the process described in Example 1, Step A, using 2-bromo-1-(2,4-dimethyl-5-pyridyl)-1-propanone (Coapound 27) as the ketone and N-(dicyclopropylmethyl)-N-propylthiourea (Compound 66) as the thiourea.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[O:29]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH:46]=[O:47]>C1COCC1.CCCCCC.CCOCC>[OH:47][CH:46]([C:42]1[S:41][CH:45]=[CH:44][CH:43]=1)[C:36]([CH3:40])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:37]([OH:39])=[O:38]
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: O=Cc1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)(C(=O)O)C(O)c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
To a 2.0 M solution of LDA in THF/heptane/ethyl benzene (200 mL, 408 mmol) cooled by an ice/acetone bath, a 0.75 M solution of 2-phenoxypropionic acid (30.8 g, 185 mmol) in THF (250 mL) was added dropwise over 30 min, keeping the reaction temperature below −10° C. After allowing the reaction mixture to stir for 15 min, a 0.75 M solution of 2-thiophenecarboxaldehyde (20.8 g, 185 mmol) in THF (250 mL) was added dropwise over the course of 1 h, maintaining the reaction temperature below −5° C. After stirring for 5 min at 0° C., HPLC analysis showed the reaction to be complete. The reaction was poured into ice water (600 mL) and ether (500 mL) was added. Hexane (1.0 L) was added and the layers were separated. The aqueous layer was further extracted with Et2O: hexane (1:2) (750 mL). The organic layers were checked for product then discarded. ethyl acetate (500 mL) was added to the aqueous layer, acidified to pH=2 with conc. HCl (18 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL). The organic layer was dried over NaCl and solvent removed in vacuo to provide 50.0 g of crude product. The product was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, 1H), 7.26 (m, 2H), 7.12 (m, 1H), 7.04 (d, 1H), 6.97 (m, 2H), 6.87 (dd, 1H), 5.37 (s, 1H), 1.40 (s, 3H); MS (EI−) 277.1 (M−1)−.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:19]2[S:23][C:22]([C@@:24]3([OH:36])[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[C:26]([CH3:35])([CH3:34])[CH2:25]3)=[N:21][CH:20]=2)[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[OH:36][C@:24]1([C:22]2[S:23][C:19]([C:12]3[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=3)=[CH:20][N:21]=2)[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[C:26]([CH3:35])([CH3:34])[CH2:25]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO[Si](C)(C)C(C)(C)C)cc([N+](=O)[O-])c3)s2)CC1(C)C
Agent: F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc([N+](=O)[O-])c3)s2)CC1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of the product of Step 3 (4.4 g, 8.23 mmol) in acetonitrile (20 mL) was added triethylamine trihydrofluoride (4 mL, 24.7 mmol). The mixture was stirred for 5 h at room temperature, then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2×), and the combined organics were dried over sodium sulfate, filtered, and concentrated to give methyl(1S,4R)-4-hydroxy-4-{5-[3-(hydroxymethyl)-5-nitrophenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate (3.5 g, 7.9 mmol, 96% yield) as an orange-maroon oily foam. MS ESI: [M+H]+ m/z 421.1.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].CC1C=CC(S(O[CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:25]=3)[O:20]2)(=O)=O)=CC=1.FCCCN>>[F:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:25]=2)[O:20]1
Reactant: NCCCF
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCCF)CC2

Procedure:
3-fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on a SCX-3 ion exchange column (TEA/MeOH). [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0561 mmol) and 3-fluoropropan-1-amine (0.15 M in MeOH/TEA:4/1, 5 ml) was heated under microwave radiation at 120° C. for 1 h 20 min. MS m/z (rel. intensity, 70 eV) 301 (M+, 3), 131 (8), 91 (9), 90 (bp), 86 (18), 70 (18).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]([CH3:30])[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:12]>CO>[CH2:14]([O:13][C:11]([CH:10]([NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[CH3:30])=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCOC(=O)C(C)Br
Reactant: Nc1cccc(O)c1
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC(=O)C(C)Nc1cccc(O)c1
Reaction time: 3 h

Procedure:
Into 25 g of m-aminophenol while heating under reflux in 200 ml of methanol was added dropwise over a period of 3 hours a solution of 37 g of hexadecyl α-bromopropionate in 100 ml of methanol. After completion of the addition, the refluxing was continued for an additional 3 hours, the methanol was then distilled off, the concentrate was dissolved in 300 cc of ethyl acetate, and the solution was washed twice with 300 cc of 10% hydrochloric acid. The ethyl acetate phase was washed with water, dried over sodium sulfate and was then concentrated. The concentrate was cooled with ice, whereby pale yellow crystals were deposited. The yield was 25 g and the melting point was 35°-40° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([OH:31])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:31][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: OC1CCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC3CCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and cyclobutanol (53.6 mg; 0.736 mmol), example 64 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[N:26]([CH2:27][CH2:28]OS(C)(=O)=O)[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CO.ClCCl>CN(C)C=O>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[N:26]([CH2:27][CH2:28][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2ccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine imidazole (0.08 g, 1.2 mmol) and dimethylformamide (2 mL). Cool in an ice bath and add sodium hydride (0.04 g, 60% i oil, 1.2 mmol). After 30 minutes, warm to ambient temperature. Add a solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.35 g, 0.80 mmol) in dimethylformamide (2 mL). Heat to 75° C. After 12 hours, partition the reaction mixture between water and dichloromethane. Extract the organic layer twice with water, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia to give 1-(t-butoxycarbonyl)-4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.44 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]2[C:6]3[N:14]=[C:13]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([O:21][CH2:22][CH3:23])[C:7]=3[NH:8][C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH2:22]([O:21][C:11]1[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[NH2:36])[CH:3]=[C:4]([O:24][CH3:25])[C:5]=3[C:6]=2[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:12]=1)[CH3:23]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)cc(OC)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(-c3ccccc3N)cc(OC)c12

Procedure:
70 mg (0.17 mmol) 7-bromo-4-ethoxy-9-methoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole, 56 mg (0.26 mmol) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 119 mg (0.51 mmol) K3PO4×H2O, 2.8 mg (6.8 μmol) S-Phos and 0.8 mg (3.4 μmol) Pd(OAc)2 in 6 ml dioxan were heated in a microwave oven to 120° C. for 1 h. Then, the solvent was removed and after LC (CH2Cl2:MeOH, 0-20%) 20 mg (24%) of the title substance was obtained. ESI-MS [m/z]: 419 [M+H]+
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH:19]([C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[O:28][CH3:29])[CH2:18][CH2:17][CH2:16][C:15]2=[O:30])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO>[CH3:29][O:28][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH:19]1[N:14]([CH2:13][C:12]2[CH:31]=[CH:32][C:9]([OH:8])=[CH:10][CH:11]=2)[C:15](=[O:30])[CH2:16][CH2:17][CH2:18]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-(4-(benzyloxy)benzyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one (74 mg; 0.17 mmol), and 10% Pd(C) (35 mg) in anh. EtOH (3 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 15 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and additional drying under HV afforded 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one as a yellow oil. LC-MS (conditions E): tR=0.62 min.; [M+H]+: 342.20 g/mol.
Reaction SMILES: C([C:3]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[OH-].[Na+]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:13]([NH:12][C:10]2[CH:11]=[CH:3][C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=2)=[O:14])[CH:16]=1
Reactant: CCc1cc(NC(=O)c2cccnc2)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2cccnc2)cc1

Procedure:
A mixture of 12.0 g (0.044 mol) of ethyl 4-[(3-pyridinylcarbonyl)amino]benzoic acid, 65 ml of 2N sodium hydroxide and 120 ml of methanol is refluxed for 0.75 hour. The solvent is removed and the residue extracted with diethyl ether. The residue is diluted with water and solid citric acid is added until the pH is 4-5. The mixture is filtered and the solid washed with water and air dried to give crystals, m.p. 307°-310° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10](Cl)[C:11]2[O:20][C:19]3[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:14]=3[C:12]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([OH:35])C=CC=CC=1>>[CH2:1]([C:8]1[CH:9]=[C:10]([OH:35])[C:11]2[O:20][C:19]3[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:14]=3[C:12]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Cc4ccccc4)cc3c2C1
Reactant: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(Cc4ccccc4)cc3c2C1
Yield: 71 %

Procedure:
The product of step C (150 mg, 0.37 mmol) was converted to the phenol derivative following the procedure of Example 54, step A. The crude product was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing tert-butyl 8-benzyl-6-hydroxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (100 mg, 71%) as an off-white solid which was converted directly to the methyl ether derivative following the procedure of Example 54, step B. Purification by column chromatography (SiO2, 85:15 hexanes/ethyl acetate) provided tert-butyl 8-benzyl-6-methoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (80 mg, 58%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.32-7.27 (m, 2H), 7.23-7.16 (m, 3H), 6.84 (br s, 1H), 6.61 (s, 1H), 4.50 (br s, 2H), 4.04 (s, 2H), 3.95 (s, 3H), 3.80 (t, J=5.4 Hz, 2H), 2.88-2.81 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30][C:31](=O)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1Cc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1Cc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
To ethyl 1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate (23.8 mg, 0.048 mmol; see example 195) in tetrahydrofuran (1 ml) was added lithium aluminium hydride in tetrahydrofuran (0.143 ml, 0.143 mmol) and the reaction mixture was refluxed for 2 h. Cooled down to room temperature and a 2N sodium hydroxide was slowly added and extracted twice with dichloromethane, washed with sodium bicarbonate and brine, dried, filtered and evaporated to obtain the crude material as white solid, that was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane over 25 min to afford N-(2-(3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass. m=6.4 mg (23%)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].C([Li])CCC.[I:20]I>C1COCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:20])[CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1cccc(Br)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred -78° C. solution of 3-bromobenzaldehyde diethyl acetal, prepared as in step 1, (1.0 g, 3.8 mmol) in THF (10 mL) was added n-butyllithium (1.7 mL, 4.25 mmol, 2.5M in hexanes). The cold reaction mixture was stirred 0.5 hours followed by the addition of a THF (5 mL) solution of iodine (1.09 g, 4.25 mmol). The ice bath was removed and the reaction allowed to warm to ambient temperature. Saturated NH4Cl was added and the mixture diluted with hexanes. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with 5% ethyl acetate-hexanes to afford 1.0 g of 3-iodobenzaldehyde diethyl acetal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]([OH:13])=[O:12].[H-].[Na+].[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1)[CH:8]=[C:7]2[C:11]([OH:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reactant: O=C(O)c1c[nH]c2c(Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 134.2 %

Procedure:
To a solution of 7-chloro-1H-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in dimethyl-formamide (100 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydropyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50° C. with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2×100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:18][CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(C)C)c2c(c1)OC(C)(C)C2
Temperature: 85 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (167 mg, 0.75 mmol) in DMF (3 mL) was added 1-bromo-2-methylpropane (0.090 mL, 0.83 mmol) and cesium carbonate (520 mg, 1.6 mmol). The reaction mixture was stirred at 85° C. for 2 hr and cooled to room temperature. The mixture was quenched with H2O (10 mL), extracted with EtOAc (2×10 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give colorless oil (193 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1 H) 7.05 (s, 1 H) 3.89 (s, 3 H) 3.80 (d, J=6.57 Hz, 2 H) 2.99 (s, 2 H) 2.02-2.16 (m, 1 H) 1.49 (s, 6 H) 1.04 (s, 3 H) 1.02 (s, 3 H); LCMS for C16H22O4 m/z 279.10 (M+H+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]2[S:25][C:26]([CH2:28][NH:29][CH3:30])=[CH:27][C:15]=2[N:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Cl:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:16]2[S:25][C:26]([CH2:28][N:29]([CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH3:30])=[CH:27][C:15]=2[N:14]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To a solution of 1-methanesulfonyl-piperidine-4-one (173 mg; prepared from N-BOC-piperidone by reaction of piperidone-4-one TFA salt with methane sulfonyl chloride) stirring in anhydrous 1,2-dichloroethane (10 ml), was added 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-ylmethyl methylamine (291 mg; as prepared from 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-carbaldehyde and methylamine under reductive amination conditions), followed by glacial acetic acid (59 μl). Sodium triacetoxyborohydride (269 mg) was added in several aliquots and then stirred for 12 hours at room temperature. The reaction mixture was diluted with dichloromethane (30 ml) and washed with 50% sodium hydrogen carbonate solution, brine, and dried (MgSO4). The solvents were removed in vacuo to give a residue which after purification by flash silica chromatography gave (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-(1-methanesulphonyl-piperidin-4-yl)-methyl-amine (408 mg), which was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole, to give, after flash silica purification the title compound (55 mg) as a white solid.