Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[C:8]2[C:3](=[C:4]([S:13]([OH:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=2[NH2:12])[CH:2]=1.[OH-].[Na+:18].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>O>[Na+:18].[OH:11][C:9]1[CH:10]=[CH:1][CH:2]=[C:3]2[C:8]=1[C:7]([NH:12][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=1)=[CH:6][CH:5]=[C:4]2[S:13]([O-:16])(=[O:15])=[O:14]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(S(=O)(=O)O)c2cccc(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(O)c12)c1cccc([N+](=O)[O-])c1
Reaction time: 0.08 h

Procedure:
A 43 g portion of recrystallized 8-amino-1-naphthol-5-sulfonic acid is suspended in 80 ml of water and 180 ml of 1N sodium hydroxide is added, then 66.6 g of m-nitrobenzoyl chloride is added all at once, washing in with a small amount of ether. The mixture is shaken for 5 minutes and another 180 ml of 1N sodium hydroxide is added with shaking for 1/2 hour. The latter addition of sodium hydroxide and shaking is repeated two more times. The resulting solution is filtered and the filtrate is made acid to Congo Red with hydrochloric acid, a precipitate forms which is collected by filtration. The solid is stirred with about 500 ml of ether and is filtered. This operation is repeated. The ethereal layer is then removed by vacuum siphoning and the solid is then dissolved in about 350 ml of hot water which is allowed to cool to give the product as a green solid which is collected by filtration. The product is then washed with saturated saline solution, 50% ethyl alcohol, absolute ethyl alcohol and ether.
Reaction SMILES: Br[C:2]1[NH:21][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=[O:18])[S:17][C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+].CN(C)CCN>CS(C)=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[NH:21][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:20]=[CH:19][C:14]5[NH:15][C:16](=[O:18])[S:17][C:13]=5[CH:12]=4)[C:4]=3[CH:3]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(Br)cc34)cc2s1
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(S(=O)(=O)c5ccc(Cl)cc5)cc34)cc2s1
Yield: 3.5 %

Procedure:
A mixture comprising 50 mg (138 μmol) 6-[(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1,3-benzothiazol-2(3H)-one (prepared according to example 8), 0.6 mL dimethyl sulfoxide, 109.7 mg sodium 4-chlorobenzenesulfinate, 7.7 mg (mu-benzene-1,2,3,4-tetrayl-1 kappa2C1,C2:2kappa2C3,C4)[bis(trifluoromethanesulfonatato-kappaO)]dicopper, 2.97 μL N,N-dimethylethane-1,2-diamine was heated at 120° C. for 2 hours to give after chromatography 2.2 mg (3%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[CH2:12]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCCCCCCCc1ccc(N)cc1
Product: CCCCCCCCc1ccc(NCc2c[nH]c3ccccc23)cc1
Yield: 52.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 1H-indole-3-aldehyde (1.5 g) and 4-octylaniline (2.1 g) as starting materials, [(1H-indol-3-yl)methyl](4-octylphenyl)amine (1.8 g) was obtained.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([CH:18](N(C)C)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[OH:28])([CH3:7])([CH3:6])[CH3:5].C(OC)(C)(C)C>O.S1(CCCC1)(=O)=O>[NH2:2][C:1]1[O:28][C:9]2[C:8]([C:4]([CH3:6])([CH3:5])[CH3:7])=[CH:13][C:12]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:11][C:10]=2[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C(c1ccccc1)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c2oc(N)c(-c3ccccc3)c2c1
Temperature: 120 °C
Yield: 99.5 %

Procedure:
A solution of 0.98 g (20,0 mmol) of sodium cyanide in 2.0 ml of water is added to a solution of 3.39 g (10,0 mmol) of 2,4-di-tert-butyl-6-(dimethylaminophenyl-methyl)-phenol [compound (201), Table 2, prepared according to Example 2a in WO-A-99/67232] in 10 ml of sulfolane. The reaction mixture is then maintained at 120° C. for one hour. After cooling to room temperature, the reaction mixture is poured into 80 ml tert-butyl-methylether and washed three times with water. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. The residue yields 3.20 g (99%) of 2-amino-3-phenyl-5,7-di-tert-butyl-benzofurane (compound (301), Table 3), m.p. 174-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH2:25])=[S:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.Br[CH:34]([CH3:38])[C:35](=O)[CH3:36].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[S:24][C:34]([CH3:38])=[C:35]([CH3:36])[N:25]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(N)=S)cc3)c2cc1OC
Reactant: CC(=O)C(C)Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Nc4nc(C)c(C)s4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}thiourea (50 mg) was dissolved in dimethylformamide (5 ml) to prepare a solution. Triethylamine (43 mg) and 3-bromo-2-butanone (43 mg) were added to the solution, and the mixture was stirred at room temperature for 3 hr. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was then washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The crude thus obtained was purified by column chromatography on silica gel using chloroform/methanol for development to give the title compound (42 mg, yield 73%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2.[OH-].[K+].[TeH2].[Na].[Te].[BH4-].[Na+]>C(O)C>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH2:33][CH2:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH:39]=[CH:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=Cc1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (965 mg), benzo[b]furan-5-carbaldehyde (350 mg) and ethanol (10 ml) is added dropwise a 50% aqueous potassium hydroxide solution (2 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent, and to the residue are added water and diisopropyl ether. The mixture is stirred, and the aqueous layer is collected. The aqueous layer is neutralized with a 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The resulting organic layer is washed with water, dried, and evaporated to remove the solvent to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone. This product is added to a solution of sodium tellurium hydride in ethanol (15 ml), which is previously prepared from tellurium (383 mg) and sodium borohydride (270 mg), and the mixture is reacted at room temperature for 2.5 hours. The insoluble materials are removed by filtration, and to the filtrate are added water and ethyl acetate. The mixture is stirred, and the organic layer is collected, washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (480 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][O:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[O:28][CH2:27][C:26]1[N:5]([C:4]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cc(F)cc(F)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.81 g, 4.13 mmol) in DCM (15 mL) was added trimethylaluminium (6.2 mL, 12.4 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3,5-difluorophenoxy)acetamido)but-2-enoate (1.18 g, 4.14 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 12 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale brown solid (1.08 g, 61%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:15]#[N:16])[N:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:1]([O:3][C:4](=[O:17])[C:5]([N:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[C:15]([NH2:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)C(C#N)N(C)Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(=C(N)c1ccccc1)N(C)Cc1ccccc1

Procedure:
Ethyl-2-[methyl(phenylmethyl)amino]-cyanoacetate (0.049 mol, 11.3 g) was dissolved in 300 mL of ether and added to 32 mL of 3M PhMgBr, and the resulting mixture was refluxed for 18 h. The reaction was cooled, quenched with sat. NH4Cl solution and extracted with ether. The organics were dried, concentrated, and chromatographed using 1:1 hexanes:ethyl acetate to give 5 g of product. 1H NMR (300 MHz) CDCl3: 7.6-7.2 (m, 10H), 5.01 (s, 1H), 4.27 (t, 2H), 3.59 (s, 2H), 2.73 (t, 2H), 2.31 (s, 3H).
Reaction SMILES: [CH:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:10][S:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])=[O:22])=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)C1CCCCC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The general method of procedure A was followed with cyclohexanesulfonamide (1.89 g), acetone (5 ml), 1N sodium hydroxide (11.6 ml). After stirring overnight at room temperature, the mixture was cooled in an ice bath and 4-chlorophenyl isocyanate (1.89 g) dissolved in acetone (5 ml) was added. The mixture was warmed to room temperature and stirred two days, filtered, and the separated white solid washed with water. The filtrates were combined and treated with glacial acetic acid (1 ml) followed by addition of water. The resulting solid was collected by filtration, washed with water and air dried to provide 2.57 g of a tan powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[CH:14]=O)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=C(B(O)O)C=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][NH:31][CH3:30])[CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=Cc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CN
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1cccc(B(O)O)c1
Product: CNCc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1

Procedure:
3-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (247 mg, 0.80 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 3-formylphenylboronic acid) was reacted with methylamine (4.91 mmol) as described for Compound PPP to yield 8-fluoro-2-(3-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 193 mg (74%) as an off-white solid: m.p. 270-272° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.34 (s, 3H), 3.05 (m, 2H), 3.39 (m, 2H), 3.78 (s, 2H), 7.42 (m, 5H), 7.61 (br s, 1H), 8.26 (br t, 1H), 11.70 (br s, 1H). HRMS (MALDI, MH+) Calcd for C19H18N3° F.: 324.1512. Found: 324.1498. Anal. (C19H18N3OF.1.5 H2O.0.35 CHCl3) C, H, N.
Reaction SMILES: C([O:6][C:7]1[C:16]([CH2:17][CH:18]=[CH2:19])=[C:15]2[C:10]([CH:11]=[C:12]([CH2:21][CH3:22])[C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1)(=O)CCC>CO.[Pd]>[CH2:21]([C:12]1[C:13](=[O:20])[O:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:6])[C:16]=2[CH2:17][CH2:18][CH3:19])[CH3:22]
Reactant: C=CCc1c(OC(=O)CCC)ccc2cc(CC)c(=O)oc12
Agent: [Pd]
Solvent: CO
Product: CCCc1c(O)ccc2cc(CC)c(=O)oc12

Procedure:
7-Butyroyloxy-3-ethyl-8-(2-propenyl)coumarin (Step B; 95 mg) dissolved in methanol was reacted with 10% Pd/C under an atmosphere of hydrogen gas for several hours. The crude mixture was loaded directly onto a flash column containing silica gel and eluted with 20% ethyl acetate/hexane. This provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:20][O:19]C(=O)[NH:17]3)[C:4]=2[CH:3]=1.[OH-].[K+]>CO.O1CCOCC1>[NH2:17][C@@:5]1([CH2:20][OH:19])[C:4]2[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][C:8]([I:16])=[CH:9][CH:10]=2
Reactant: O=C1N[C@@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Reaction time: 24 h
Yield: 37 %

Procedure:
In a 350-mL resealable vessel, the (S)-2′-bromo-7′-iodospiro[oxazolidine-4,9′-xanthen]-2-one (11 g, 24.02 mmol) was dissolved in 1:1 MeOH-dioxane (160 mL). Aqueous KOH (5 M, 48.0 mL, 240 mmol) was added. The vessel was sealed and placed in a 105° C. oil bath. After 24 h, the reaction was concentrated to remove the MeOH and most of the dioxane. The residue was diluted with water (200 mL) and the aqueous phase was extracted with 5% MeOH-DCM (4×200 mL). The organics were combined, washed with dilute brine (35 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (1.5% MeOH/DCM) to afford (S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g, 8.89 mmol).
Reaction SMILES: [F:1][C:2]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:18]=[C:12]3[CH:11]=2)=[CH:8][CH:7]=[C:6]([F:26])[C:3]=1[CH:4]=[O:5].[C:27]([Mg]Br)#[CH:28]>O1CCCC1>[F:1][C:2]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:18]=[C:12]3[CH:11]=2)=[CH:8][CH:7]=[C:6]([F:26])[C:3]=1[CH:4]([OH:5])[C:27]#[CH:28]
Reactant: O=Cc1c(F)ccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1F
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1c(F)ccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1F
Yield: 58.7 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.270 g (0.77 mmol) of 2,6-difluoro-3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde obtained in stage 6.1, in solution in 15 ml of tetrahydrofuran, followed by addition of 4.60 ml (2.30 mmol) of an ethynylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and dichloromethane (1/3), 0.171 g (57%) of the expected product is obtained in the form of a pale yellow powder.
Reaction SMILES: Cl[CH:2]([CH3:16])[C:3](=[O:15])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:20][CH2:19][CH2:18][S:17][CH:2]([CH3:16])[C:3](=[O:15])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCCON=C(C(=O)OCC)C(=O)C(C)Cl
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCON=C(C(=O)OCC)C(=O)C(C)SCCO
Temperature: 20 °C
Reaction time: 1.33 h
Yield: 85.1 %

Procedure:
Ethyl 4 chloro-3-oxo-2-n-propoxyiminovalerate (180.0 g.) was added to a stirred solution of 2-mercaptoethanol (71.6 g.) in chloroform (1.8 l.), and then a solution of triethylamine (93.1 g.) in chloroform (200 ml.) was added to the solution over 5 minutes. The solution was stirred at 20° C. for 80 minutes. After washing the resultant mixture with 10% hydrochloric acid twice, a saturated aqueous solution of sodium bicarbonate twice and water in turn, the solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-(2-hydroxyethylthio)-3-oxo-2-n-propoxyiminovalerate (178.7 g.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([C:25]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=4[CH3:37])([CH3:29])[CH2:26][CH2:27][CH3:28])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:36].[CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([O:24][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][N:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH:40]4[CH3:39])=[CH:22][C:21]([C:25]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=4[CH3:37])([CH3:29])[CH2:26][CH2:27][CH3:28])=[CH:20][C:15]=3[O:16][C:17]([CH3:18])([CH3:19])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCCN1CCCC(=O)O
Reactant: CCCC(C)(c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1)c1cc(Cl)ccc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC(C)(c1cc(OC(=O)CCCN2CCCCC2C)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1)c1cc(Cl)ccc1C

Procedure:
2-Benzyl-5,5-dimethyl-10-hydroxy-8-(2-methyl-5-chlorophenyl-1-methylbutyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)-butyric acid hydrochloride and dicyclohexylcarbodiimide in equimolar amounts are reacted as in Example 7 to give the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(C2CC2)=NC=C(CC)N=1>>[CH:1]1([C:3]2[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=2)[CH2:23][CH2:2]1
Reactant: CCc1cnc(C2CC2)c(Cl)n1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2-cyclopropyl-5-ethylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.93-1.02, 1.24-1.30, 1.72-1.81, 2.61-2.68, 3.06-3.30, 4.79-4.84, 5.36, 5.58, 7.24-7.35, 7.66; MS (ESI+) for C18H21N3O m/z 296 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a 10 mL round-bottomed flask, tert-butyl 4-(3-(3-(3,5-difluorophenyl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (107.5 mg, 0.19 mmol) obtained in Step 2 of Example 64 and CH2Cl2 (2 mL, 0.1M) were charged. Trifluoroacetic acid (0.6 mL, 40.0 eq) was added dropwise over 5 min at 0° C. After being stirred for 2 h, the mixture was quenched with H2O and washed with CH2Cl2. The aqueous layer was basicified to pH 9 with a 15% NaOH solution and extracted with CH2Cl2. The extracts were concentrated in vacuo to provide the title compound (80 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>[Ni].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)c(Cl)c2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Yield: 86.2 %

Procedure:
4-[2-(3,4-dichlorophenyl)ethenyl]nitrobenzene (34.0 g, 116 mmol) and 2 g of Raney nickel in 510 ml of tetrahydrofuran were shaken under hydrogen at 15 psi (103.4 kPascal) until four equivalents of hydrogen were consumed. The catalyst was removed by filtration, and the resulting filtrate evaporated in vacuo to yield a residual tan solid. Recrystallization from hexane yielded 26.6 g (86%) of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine, mp 72°-74° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>C(Cl)Cl>[N:19]1([CH2:18][CH2:17][CH2:16][N:11]2[C:12](=[O:15])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCN2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1CCNCCN1CCCN1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
A solution of 7.3 g (21.50 mmol) of 5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester was in 140 ml CH2Cl2, cooled to 0° C. and treated with 54 ml (215 mmol) of HCl solution (4 M dioxane), then warmed to RT. After 3 h, 40 ml of MeOH were added to dissolve the precipitation and stirring was continued over night. The solution was evaporated, dissolved in aq. sat. NaHCO3. solution, the water evaporated and the solid extracted with in CH2Cl2:MeOH 9:1. Concentration afforded the title compound 5.0 g (97%) as yellow oil. MS: 240.1 (MH+).