Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][OH:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][O:16][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(=CNCCO)C(=O)c1cc(I)cc(F)c1F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate (2.0 g, 4.7 mmol) obtained in Step 2 was dissolved in DMF (10 ml), imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49 g, 9.9 mmol) were added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give the object product (2.3 g, yield 91%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1COCC1>[C:15]([NH:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13])(=[O:17])[CH3:16]
Reactant: NC[C@H](O)CCl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H](O)CCl
Reaction time: 0.08 h

Procedure:
Triethylamine (10.5 ml, 75.3 mmol, 1.11 eq) is added to a slurry of (S)-1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9.938 g, 68.059 mmol) in THF (80 ml) at −40° and the mixture stirred for 5 min at −40°. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at −40° and the mixture allowed to warm to 20-25° over 1.5 hrs. The precipitate is removed by filtration with reduced pressure and washed with THF. The filtrate is treated with magnesol (5.69 g), which is removed by filtration with reduced pressure and washed with THF (2×60 ml). The filtrate is then concentrated under reduced pressure. The concentrate is purified by flash chromatography (silica gel; eluting with a gradient of 75-100% ethyl acetate/cyclohexane) to give the title compound, NMR (CDCl3) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and 7.09 δ; CMR (CDCl3) 28.00, 43.31, 46.52, 70.65 and 172.40 δ; MS (CI, NH3), M/Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152 (48.1); [α]26D=7.44 (c=1.00, H2O).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[CH3:27][Mg]Br.[Cl-].[NH4+].O>C1C=CC=CC=1>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15]([OH:17])([CH3:16])[CH3:27])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 3α-acetoxy-5α-pregnan-20-one (120 mg, 360.5 g/m, 0.32 mmol) in 25 mL of dry benzene, was added 4.6 mL of 3M methylmagnesium bromide dropwise. After the addition of methylmagnesium bromide was completed, the reaction mixture was allowed to stir at room temperature for 18 h and then refluxed for 2 h. The excess methylmagnesium bromide was decomposed by dropwise addition of 30 mL of saturated ammonium chloride solution in an ice bath. The solution product was poured into water and extracted with chloroform twice. The extracts were dried over magnesium sulfate and evaporated to give 110 mg of crude product. The product was recrystallized in methanol to give 83 mg of 3α,20-dihydroxy-20-methyl-5α-pregnane.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.[CH3:19][N:20]=[C:21]=[S:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[S:22]
Reactant: CN=C=S
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Solvent: c1ccccc1
Product: CNC(=S)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reaction time: 1 h

Procedure:
To a stirred solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (5.0 g) in dry benzene (18 ml) is added methylisothiocyanate (3.1 g) in dry benzene (10 ml). After one hour, the product begins to separate. The mixture is stirred overnight and diluted with hexane (18 ml). The product is filtered, washed with hexane and dried to yield a solid. The solid is twice recrystallized from benzene to yield (3.0 g, 46%) as a solid, mp 165°-166°.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23]>CN(C=O)C.[Cu-]=O>[Cl:11][C:12]1[CH:17]=[C:16]([S:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:23])([F:25])[F:24]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-mercaptobenzoic acid (0.308 g), (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (0.786 g) and copper(I) oxide (0.1 43 g) in DMF (5 ml) was stirred and heated under reflux for 1 hour. More 4-mercaptobenzoic acid (0.308 g) was added and heating was continued for a further 2 hours. The mixture was cooled, filtered, and the filter washed with DMF (5 ml). The filtrates were concentrated by evaporation and the residual solid was extracted with boiling ethyl acetate (2×60 ml). The extracts were absorbed onto deactivated silica (silica deactivated by treatment with 10% water) and purified by chromatography eluting with 5% methanol/ethyl acetate to give the title compound (0.803 g) as a solid. NMR: 1.63 (s, 3H), 7.31 (d, 2H), 7.5 (dd, 1H), 7.68 (d, 1H), 7.89 (d, 2H), 8.22 (d, 1H), 9.8 (brs, 1H); MS (ESP−): 418; EA: found: C, 48.2; H, 3.1; N, 3.2%; C17H13NClF3O4S requires C, 48.6; H, 3.1; N, 3.3%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCCO
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Yield: 101 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzonitrile (10 g, 0.06 mol) in THF (50 mL) was added in portions, via syringe, 3-aminopropanol (5 mL, 0.07 mol) and the mixture was stirred at room temperature. After one hour of reaction the crude mixture was evaporated to dryness and AcOEt was added (300 mL). The organic layer was washed with aqueous sodium bicarbonate (250 mL of a 4% aqueous solution) and the aqueous phase was further extracted with AcOEt (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the title compound as an orange solid (13.4 g, 99% yield) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.B([O-])([O-])O[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Cl-].[Na+].O.O.C(OCC)(=O)C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[N:7]=[C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)C=Cc1cccc(Br)n1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C=Cc1cccc(-c2ccc(C)cc2)n1
Temperature: 80 °C
Reaction time: 10 h
Yield: 92.5 %

Procedure:
In 1,2-dimethoxyethane (4 ml) were dissolved ethyl 6-bromo-2-pyridineacrylate (512 mg, 2.00 mmol) and 4-methylphenyl borate (299 mg, 2.20 mmol), and to the mixture were added sodium carbonate (424 mg, 4.00 mmol), water (2 ml) and tetrakis-(triphenylphosphine)palladium (116 mg, 0.10 mmol). The mixture was stirred at 80° C. for 10 hours. To complete the reaction, 4-tolyl borate (150 mg, 1.10 mmol) and tetrakis(triphenyl-phosphine)palladium (116 mg, 0.10 mmol) were added at 80° C. to the mixture, and the mixture was stirred for 14 hours. To the mixture was added ethyl acetate (30 ml), and the mixture was water (5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 15 g, ethyl acetate/hexane=1/19), and the desired fraction was concentrated under reduced pressure to give ethyl 6-(4-methylphenyl)-2-pyridineacrylate (495 mg, 1.85 mmol, 93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[C@@H](C)O>C(#N)C.ClCCl>[CH2:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(Cc2ccccc2)n1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc(Cc2cncc(N3CCNCC3)n2)cc1
Temperature: 85 °C
Reaction time: 8.5 h
Yield: 57 %

Procedure:
A mixture of the product from step 1 above (0.83 g, 4.0 mmol), piperazine (1.1 g, 12.8 mmol) and K2CO3 (0.62 g, 4.49 mmol) in acetonitrile (7 mL) was stirred at 85° C. for 8.5 h. Thr reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (20×4 cm) using CHCl3/MeOH (9:1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short (4 cm) plug of alumina using ether/MeOH (96:4) as eluent. Solvent removal in vacuo furnished 0.59 g (57%) of the title compound as an oil which became semi-solid upon refrigeration. HRMS m/z calcd for C15H18N4 (M)+ 254.1531, found 254.1527. Anal. (C15H18N4) C, H, N.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.[NH:30]1[CH:38]=[C:36]([CH3:37])[C:34](=O)[NH:33][C:31]1=[O:32]>C(#N)C.CO>[CH3:37][C:36]1[C:38]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:30][C:31](=[O:32])[NH:33][CH:34]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: c1nc[nH]n1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(=O)nc1-n1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
69 g (1 mol) of 1,2,4-triazole are suspended in 800 ml of dry acetonitrile under a protecting gas (argon). 251 g (0.95 mol) of diphenyl chlorophosphate are added to the suspension at 0°-10° C. Subsequently, in the course of 1 hour, 151.79 g (1.5 mol) of triethylamine are added dropwise before 63 g (0.5 mol) of thymine are added. The resulting suspension is stirred for 12 hours at room temperature. Finally, the mixture is heated for 5 hours at 60°-80° C. 40 ml of methanol are added to the cooled suspension and the mixture is stirred for 2 hours at room temperature. The suspension is filtered; the residue is stirred with one liter of diisopropyl ether, filtered off again by suction and stirred with 800 ml of water. The aqueous suspension is filtered and the solid residue is recrystallized from 1300 ml of dimethylformamide. 28.6 g of 5-methyl-4-(1,2,4 -triazol-1-yl)pyrimdin-2(1H)-one are obtained with melting point 275°-280° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)N.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>C(O)(C)C>[CH:9]1[C:8]2=[C:12]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:16]1[CH2:17][CH2:18][NH:13][CH2:14][C:15]3=1
Reactant: NNc1ccc2sccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: c1cc2c(ccc3[nH]c4c(c32)CNCC4)s1

Procedure:
15 g of 5-hydrazinobenzothiophene hydrochloride and 15 g of 4-piperidone are boiled in 450 ml of isopropanol under a reflux condenser for 2 hours. After cooling the mixture, the precipitate which has separated out is filtered off and suspended in 2 N NaOH. A layer of methylene chloride is introduced under the suspension and the mixture is stirred; the layers are then separated and the organic phase is washed, dried and evaporated. After recrystallisation of the residue from isopropanol, 7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole of melting point 190° is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:36]([C:35]1[C:31]([O:30][CH2:2][C:3]2[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=4)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=3[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=2)=[N:32][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=1)=[O:37]
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A mixture of methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.04 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g), anhydrous potassium carbonate (0.33 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.25 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 195-196° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzonitrile, 1.5 g (5.3 mmol) of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (MP 86-87° C.)
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:17])[C:4]2[C:9]([C:10]=1[C:11]([NH:13][CH3:14])=[O:12])=[CH:8][CH:7]=[C:6]([O:15]C)[CH:5]=2.B(Br)(Br)Br.C(Cl)Cl>>[CH3:14][NH:13][C:11]([C:10]1[C:9]2[C:4](=[CH:5][C:6]([OH:15])=[CH:7][CH:8]=2)[N:3]([CH3:17])[C:2]=1[Cl:1])=[O:12]
Reactant: CNC(=O)c1c(Cl)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)c1c(Cl)n(C)c2cc(O)ccc12
Yield: 58.4 %

Procedure:
This material was prepared by reaction of 2-chloro-6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75b (0.38 g, 1.4 mmole) with 1.0 M BBr3 in CH2Cl2 (4.19 ml, 4.19 mmole) in a manner as previously described for example 1d to give an off-white solid (0.195 g, 85%). 1NMR (300 MHz, CD3OD) δ 7.61 (1H, d, J=8.3 Hz), 6.65 (1H, s), 6.62 (1H, d, J=2.1 Hz), 3.56 (3H, s) 2.85 (3H, s); ESIMS (MH+): 239.00.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]([C:17]4([OH:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4([OH:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1(O)CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc12

Procedure:
A suspension of Example 126B (0.144 g, 0.241 mmol) and 50% sodium hydroxide (0.064 mL, 1.205 mmol)/water (0.064 mL) in dioxane (1 mL) was heated at 80° C. for 4 hours. The mixture was diluted with ethyl acetate and dried over magnesium sulfate, filtered and concentrated. The crude mixture was used in the next step without further purification. LCMS: 442.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH:10]([CH3:25])[CH2:9]1)C1C=CC=CC=1>[C].[Pd].C(O)(=O)C>[CH3:25][CH:10]1[CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CCC1n1c(=O)ccc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CNCCC1N1C(=O)CCc2ccccc21
Yield: 65.4 %

Procedure:
Acetic acid (30 ml) and 1-(1-benzyl-3-methyl-4-piperidinyl)carbostyril (2.1 g) are added to 10% palladium-carbon (0.5 g) and the mixture is subjected to catalytic reduction at 80° C. under atmospheric pressure. After the catalytic reduction, 10% palladium-carbon is filtered off and the filtrate is concentrated under reduced pressure. Water is added to the residue and the mixture is basified with aqueous sodium hydroxide solution and then extracted with dichloromethane. After washed with water, the extract is dried with magnesium sulfate and the solvent is distilled off under reduced pressure to give 1-(3-methyl-4-piperidinyl)-3,4-dihydrocarbostyril (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH:31]1([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH:39]2[CH2:43][NH2:44])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CC(C)=O.O>[CH:31]1([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH:39]2[CH2:43][NH:44][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: NCC1CCCN1CC1CCCCC1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NCC2CCCN2CC2CCCCC2)c1OC
Reaction time: 0.5 h

Procedure:
26.1 g of 2,3-dimethoxy-5-sulphamoyl-benzoic acid (0.10 mole), 40 ml of water, 200 ml of acetone and 10.1 g of triethylamine (0.10 mole) are placed in 500 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to between 0° and +5° C. and 10.9 g of ethyl chloroformate (0.10 mole) is added drop by drop. It is agitated for 1 hour 30 minutes with the temperature kept at about +5° C., then 19.6 g of 1-cyclohexylmethyl-2 aminomethyl pyrrolidine (0.10 mole) is added drop by drop. A precipitate forms progressively as more and more is added. The reaction medium is then agitated at room temperature, after which it is left to stand. The crystals are filtered, washed three times with water then with 100 ml of 10% ammonia and dried in an oven at 50° C. 50 g is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:36][C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[N:34][CH:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:36][C:32]([CH2:30][CH3:31])=[CH:33][N:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191.5 mg; compound B26) and HBTU (167 mg) in DCM (3 ml) is added DIPEA (0.28 ml) and the mixture is stirred for 1 h at RT. After 1 h an additional amount of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (40 mg) is added and the mixture is stirred for 15 min in order to complete the reaction. Subsequently the solvent is removed and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc/MeOH, 97.5/2.5 (v/v)] and afterwards by preparative HPLC to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][O:17]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:11]2[CH2:16][CH2:15][C:14]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1nccc(N2CCC3(CC2)OCc2ccccc23)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (1 g, 3.655 mmol), spiro[isobenzofuran-1(3H),4′-piperidine], hydrochloride [CAS 37663-44-8] (0.83 g, 4.386 mmol) and DIPEA (1.273 ml, 7.309 mmol) in CH3CN (9 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution) and extrated with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (0.199 g, 16%) as a white solid. M.P. 160.8° C.