Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:7][CH:6]=1.[Se](=O)=[O:20].C(Cl)Cl.CO>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[N:7][CH:6]=1)=[O:20]
Reactant: COC(=O)Cc1cnc(NC(=O)OC(C)(C)C)s1
Reactant: O=[Se]=O
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Yield: 23.3 %

Procedure:
Methyl(2-tert-butoxycarbonylamino 1,3-thiazole-5-yl)acetate (4.08 g, 15 mmol) in dioxane (60 ml) was reacted with selenium dioxide (4 g, 36 mmol) at reflux for 45 minutes. The mixture was cooled, CH2Cl2/MeOH 8/2 (150 ml) was added, the insoluble material was filtered, the organic phase was washed with a saturated solution of sodium bicarbonate, and extracted with CH2Cl2, dried, purified by chromatography over alumina, eluant CH2Cl2/MeOH 9/1 to give title compound (1 g, 23%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CO[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].[C:36]([O-])([O-])=[O:37].[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:32]4[CH:31]=[CH:30][C:29]([O:37][CH3:36])=[CH:28][C:27]4=[C:25]=[O:26])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=CC(=C=O)C(c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)C=C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (1.70 g), 4-(methoxycarbonyl)phenyl boronic acid (997 mg), in N,N-dimethylformamide (50 mL) a 2 M aqueous Na2CO3 solution (5.77 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (377 mg) is added. The resulting mixture is stirred for 3 h at 90° C. After cooling to room temperature, water is added and the aqueous phase is extracted with ethyl acetate. The organic phase is concentrated and the residue is purified by HPLC on reversed phase (MeOH/H2O/TFA) yielding 4-[5-(4-methoxy-carbonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester. The material was mixed with methanol (20 mL) and 1 M aqueous sodium hydroxide (11.5 mL). After heating for 5 h to 55° C. the mixture was cooled to 20° C. and acidified with 1 M aqueous HCl. The precipitate formed was filtered off, washed with water and dried in vacuo. LC (method 5): tR=1.59 min; Mass spectrum (ESI+): m/z=410 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)=[CH:8][O:9][C:5]=2[CH:4]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:29][CH2:28][CH:27]([NH:26][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][C:7]2[C:6]4[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:9][CH:8]=2)[CH:20]=[CH:19][CH:18]=3)=[O:22])[CH2:32][CH2:31]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 120) and amine 14.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>C(O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([NH2:8])=[CH:7][C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][C:4]=12
Reactant: Nc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Reactant: C1COCCN1
Solvent: CCO
Solvent: O
Product: Nc1cc(N2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
5-chloro-3-[(2,3-dichlorophenyl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (1.7 g, 4.43 mmol) and morpholine (1.36 g, 15.6 mmol) were mixed in ethanol (10 mL) in a microwave tube. The reaction mixture was irradiated (microwave) and stirred at 150° C. for 3 hours. Reaction mixture was dropped into cold water (100 mL) to precipitate while stirring. Precipitate was collected by filtration. It was washed with water (10 mL) and dried. The titled product was obtained. (1.90 g, 97%); LC/MS: MS (ES+) m/e 378 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (br. s., 1H) 3.45 (d, J=5.05 Hz, 3H) 3.63-3.71 (m, 4H) 4.00 (s, 2H) 5.55 (s, 1H) 7.16 (s, 2H) 7.22-7.30 (m, 1H) 7.30-7.40 (m, 1H) 7.46 (dd, J=7.83, 1.77 Hz, 1H) 7.72 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.[CH3:15][NH2:16]>CO>[CH3:15][NH:16][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
The 1-(3-chloropropoxy)-3-nitrobenzene (1.00 g, 4.65 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 493 mg (50.6%) of an oil.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].[Cl:11][CH2:12][CH2:13][CH2:14][CH:15]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+].O>C(O)C>[ClH:11].[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)N1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: Cl
Yield: 17.3 %

Procedure:
To a solution of 4.3 g (0.03 mole) 1-carbomethoxypiperazine in 10 ml of ethanol was added 10.0 g (0.036 mole) of 4-chloro-1,1-bis-(p-fluorophenyl)-butane and 5.0 g of sodium bicarbonate. The mixture was heated at reflux for 36 hours. 100 ml of water was added. The mixture was extracted twice with Et2O. The combined extracts were dried over sodium sulphate and concentrated. The residue was dissolved in ethanol-ether and the hydrochloride was precipitated with ethanolic HCl. The solid was collected by filtration and recrystallised from propan-2-ol to give 2.2 g of 1-carbomethoxy-4-[4,4-bis(p-fluorophenyl)butyl]-piperazine hydrochloride. Melting point 192°-193° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH3+:6])[CH2:4][O:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.CCN(CC)CC.[C:25]1([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>C(Cl)Cl>[O:1]=[C:2]1[C@@H:5]([NH:6][C:33](=[O:34])[CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][O:3]1
Reactant: [NH3+][C@H]1COC1=O
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N[C@H]1COC1=O
Yield: 60 %

Procedure:
To a stirred mixture of 3 (0.4 mmol) in dry CH2Cl2 (2 mL), kept at 0° C. under N2, Et3N (1.59 mmol) and 3-phenylpropionyl chloride (0.6 mmol) were added dropwise. The mixture was reacted at 0° C. for 30 min and at room temperature for 2 h, then concentrated. Purification of the residue by flash-chromatography (cyclohexane/EtOAc 1:1 to 3:7) and recrystallization gave URB783 as a white solid. Yield 60%. Mp 104-106° C. (acetone/petroleum ether). [α]D20=−13° (c 0.5, MeOH). MS (EI): m/z 219 (M+), 91 (100). IR (Nujol) 3333, 1832, 1625, 1541 cm−1; 1H NMR (CDCl3) δ 2.57 (br s, 1H), 2.99 (t, 2H), 4.34 (t, 1H, J=5 Hz), 4.43 (dd, 1H, J1=5 Hz, J2=6.5), 5.14 (m, 1H), 5.96 (br s, 1H), 7.18-7.36 (m, 5H) ppm. 13C NMR (CDCl3): δ 31.2 (CH2), 37.7 (CH2), 58.4 (CH), 66.1 (CH2), 126.5 (CH), 128.3 (2CH), 128.7 (2CH), 140.2, 168.4 (C═O), 172.5 (C═O) ppm.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[N:35]([C:38]1[NH:39][C:40]([C:44](O)=[O:45])=[C:41]([Cl:43])[N:42]=1)=[N+:36]=[N-:37]>CN(C=O)C.CCOC(C)=O>[N:35]([C:38]1[NH:39][C:40]([C:44]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:45])=[C:41]([Cl:43])[N:42]=1)=[N+:36]=[N-:37]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: [N-]=[N+]=Nc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]c(N=[N+]=[N-])nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
EDC (0.331 g, 1.726 mmol) and HOBT (0.233 g, 1.726 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.558 g, 1.569 mmol) and 2-azido-4-chloro-1H-imidazole-5-carboxylic acid (0.294 g, 1.569 mmol) in DMF (7 mL). The mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with water and brine and the organic layer was dried over sodium sulfate and concentrated to give the crude title compound (0.850 g) as a light yellow solid. This crude product was taken on to the next step without further purification.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][O:15][C:16]([C@@:18]12[CH2:24][CH2:23][C@:22]1([CH2:25]O)[CH2:21][N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:19]2=[O:35])=[O:17].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.O>[CH3:14][O:15][C:16]([C@@:18]12[CH2:24][CH2:23][C@:22]1([CH2:25][F:11])[CH2:21][N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:19]2=[O:35])=[O:17]
Reactant: COC(=O)[C@@]12CC[C@]1(CO)CN([C@H](C)c1ccccc1)C2=O
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@]12CC[C@]1(CF)CN([C@H](C)c1ccccc1)C2=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (1.98 mL, 10.7 mmol) was added to a solution of (1S,5R)-5-hydroxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester (1.30 g, 4.30 mmol) in dichloromethane in a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred for 12 hours. Then, a saturated sodium bicarbonate solution (10 mL) was added, and the mixture was stirred for 10 minutes. The reaction solution was poured into a mixture of ethyl acetate (50 mL) and water (30 mL), followed by extraction with ethyl acetate (200 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1.5:1) to give 1.26 g (96%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:57][CH:58]([CH2:63][CH2:64][CH2:65][C:66]([F:69])([F:68])[F:67])[C:59]([CH3:62])([OH:61])[CH3:60]>CN(C=O)C.O>[F:1][C:2]1([F:22])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([NH:57][CH:58]([CH2:63][CH2:64][CH2:65][C:66]([F:67])([F:68])[F:69])[C:59]([OH:61])([CH3:62])[CH3:60])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1
Reactant: Cc1cc(OCC2CC(F)(F)C2)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(O)C(N)CCCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCC2CC(F)(F)C2)c2nc(C)c(C(=O)NC(CCCC(F)(F)F)C(C)(C)O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.32 mmol) of 8-[(3,3-difluorocyclobutyl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 107A and 135 mg (0.35 mmol) of HATU were initially charged in 2 ml of DMF. 0.16 ml (0.96 mmol) of N,N-diisopropylethylamine and 70.6 mg (0.354 mmol) of rac-3-amino-7,7,7-trifluoro-2-methylheptan-2-ol hydrochloride Example 103A were then added, and the mixture was stirred at RT overnight. 7 ml of water were added, and the reaction solution was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed with 15 ml of water and with 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative RP-HPLC (acetonitrile-water+0.1% formic acid) and the product fractions were combined and concentrated to dryness. This gave 86 mg of the target compound (55% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1cccc2[nH]ccc12
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 150 °C
Yield: 85.1 %

Procedure:
4-Methyl-1H-indole (1.042 g, 7.94 mmol, 1.0 eq) was combined with 2-fluoro-benzonitrile (1.29 mL, 11.91 mmol, 1.5 eq) and potassium carbonate (2.195 g, 15.88 mmol, 2.0 eq) in DMF (7.94 mL, 1M) and heated at 150° C. for 4 hours. The reaction was then cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate. The organic extracts were washed with water and aqueous saturated sodium chloride, dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (50 g) eluting with chloroform:hexane (1:3) followed by (1:1) to give the title compound (1.57 g, 85%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(O)(=O)C.[CH2:13]([NH:15][C:16](=[O:18])[O-:17])[CH3:14].[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1>ClCCCl.C(Cl)Cl>[CH2:13]([NH:15][C:16](=[O:17])[O-:18])[CH3:14].[CH3:19][O:20][C:21]1[C:22]([Cl:1])=[CH:23][C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CCNC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(C)C1CNCC21
Temperature: 60 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
N-chlorosuccinimide (0.22 g, 1.6 mmol) and acetic acid (8 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.45 g, 1.6 mmol) in DCE (8 mL), and stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL), and washed with H2O (50 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 250 mg (51%) of the subtitle compound. MS calculated for C16H20ClNO3+H: 310, observed: 310.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[N:31]1([S:37](C2C=C(C=C(C(F)(F)F)C=2)C(O)=O)(=[O:39])=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=[C:2]([S:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)(=[O:39])=[O:38])[CH:3]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-(morpholine-4-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). Light yellow solid (34%). MS (ESI): m/z=554.14 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:10]([SiH2:12][CH2:13][Cl:14])Cl>>[CH3:10][Si:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][Cl:14]
Reactant: Br[Mg]c1ccccc1
Reactant: ClC[SiH2]C(Cl)Cl
Product: C[Si](CCl)(c1ccccc1)c1ccccc1

Procedure:
When R5 and R7 are both phenyl, about two molar equivalents of phenyl magnesium bromide is reacted with about one molar equivalent of dichloromethyl chloromethyl silane to give methyl diphenylchloromethyl silane.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][CH2:12][O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[I:34])[CH:29]=O)[CH3:21].O>O1CCCC1>[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28](/[CH:29]=[C:14](\[O:13][CH2:12][CH3:11])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:31]=[CH:32][C:33]=1[I:34])[CH3:21]
Reactant: CCOCCOc1cc(C=O)ccc1I
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOc1cc(/C=C(\OCC)C(=O)OCC)ccc1I
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
0.26 g (6.87 mmol) of sodium hydride is added portionwise to a solution at 0° C. of 1.75 g (6.87 mmol) of ethyl (diethoxyphosphoryl)ethoxyacetate (prepared according to Example 1b) in 20 mL of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at room temperature and 2 g (6.25 mmol) of 3-(2-ethoxyethoxy)-4-iodobenzaldehyde in 10 mL of tetrahydrofuran are then added dropwise. The reaction is slightly exothermic, and the reaction mixture is maintained at a temperature of 25-30° C. with an ice-water bath. When the temperature has stabilized, the reaction mixture is stirred for 24 hours at room temperature. After addition of 50 mL of water, the reaction medium is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over sodium sulfate. After evaporating under vacuum, the crude product obtained is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture to give 61.2 mg of the (E) isomer of ethyl 3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate, 1.56 g of a mixture of (Z) and (E) isomers and 270.3 mg of the isomer ethyl (Z)-3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-ethoxyacrylate in the form of yellow oils.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1.C(N(CC)CC)C.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:38]([CH3:40])[CH3:37])[CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1
Reactant: O=C1N(CC2CCNCC2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(F)c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a stirred solution of 7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (120 mg, 0.28 mmol) and triethylamine (3.9 pt, 0.028 mmol) in 5.00 mL dichloromethane was added acetone (4.1 μL, 0.56 mmol) followed with sodium triacetoxyborohydride (124 mg, 0.56 mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight, quenched with water (10.0 mL). The mixture was extracted with dichloromethane (3×30.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (2% methanol in ethyl acetate/hexane) to give 7′-fluoro-1′-[(1-isopropylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (85 mg, 69%) as a white solid, which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 157-160° C.; 1H NMR (300 MHz, CD3OD) δ 7.22-7.05 (m, 2H), 7.05-6.98 (m, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.68 (d, 1H), 3.95-3.77 (m, 2H), 3.55-3.42 (m, 3H), 3.12-2.96 (m, 2H), 2.30-2.10 (m, 1H), 2.10-1.97 (m, 2H), 1.76-1.52 (m, 2H), 1.34 (d, 6H); 13C NMR (75 MHz, CD3OD) δ 179.7, 157.6, 150.6, 150.4, 147.1, 143.9, 136.6, 125.8, 121.2, 120.3, 118.0, 103.9, 103.0, 94.3, 81.8, 60.1, 59.7, 47.6, 35.33, 35.30, 28.6, 28.5, 16.98, 16.96; MS (ES+) m/z 439.27 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([CH:24]=O)=[CH:20][CH:21]=3)[CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(O)(=O)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>ClC(Cl)C.C(OCC)(=O)C.[OH-].[NH4+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([CH2:24][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:20][CH:21]=3)[CH:16]=2)([OH:30])[C:26]([F:29])([F:27])[F:28])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(Cc1cc2nc(C=O)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reactant: C1COCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cc1cc2nc(CN3CCOCC3)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
To a solution of the aldehyde of Example 94 (0.050 g, 0.107 mmol) and 0.078 mL of acetic acid in 3.0 mL of dichloroethane was added morpholine (0.233 mL, 2.68 mmol) at 0° C. The reaction was allowed to stir at room temperature for 30 minutes. To this yellow solution was added triacetoxy sodium borohydride (0.057 mg, 0.268 mmol), then continued stirring at room temperature for 14 hours. The reaction mixture was diluted with 10 mL of ethyl acetate and 2 mL of 3% ammonium hydroxide solution. The biphasic system was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with three 20 mL portions of water, brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to give yellow oil. This crude material was applied onto a flash column and eluted with 5% MeOH—CH2Cl2, 0.5% NH4OH, to give the title compound (0.018 g, 32.0% yield) as a white foam.