Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1>CN(C=O)C.O.C(O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
N2-Butyl-8-(methoxy)-3H-purine-2,6-diamine trifluoroacetic acid salt (0.25 g) and anhydrous potassium carbonate (0.395 g) in anhydrous DMF (3 mL) was heated for 1 hour at 60° C. (external) under nitrogen, before being allowed to cool to room temperature. To the reaction mixture was then added 3-(bromomethyl) tetrahydrofuran (0.236 g) and the reaction mixture heated under nitrogen to 50° C. (external) for 18.5 hours. The reaction mixture was then diluted with water (15 mL) and extracted with diethyl ether (15 mL, 3 times). The organic layers were combined and dried over anhydrous sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated under reduced pressure to give an oil. This oil was triturated with cyclohexane and a little diethyl ether to give a solid. The cyclohexane and diethyl ether was evaporated under reduced pressure to give a white solid. The solid (0.2606 g) was dissolved in hot ethanol (2 mL). To this solution was then added water (8 mL) and the resultant suspension was heated to reflux (93° C., external) giving a solution. The solution was then allowed to cool slowly (by not removing the flask from the reaction block and turning the power off to the heating block). This gave a solid gum on cooling which when sonicated gave a white solid. This solid was isolated by filtration under suction and then dried under vacuo at 50° C., overnight. This gave the title compound (0.1043 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][CH:8]([CH3:40])[CH2:9][CH2:10][NH:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=O)[O:32]C4C=CC=CC=4)[CH:25]=3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)=[O:13].CC(C)CCNC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O>CN(C)C=O>[CH3:7][CH:8]([CH3:40])[CH2:9][CH2:10][NH:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])[CH:25]=3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)=[O:13]
Reactant: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: C1COCCN1
Agent: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Reaction time: 2 h
Yield: 34.2 %

Procedure:
N,N-dimethylformamide (5 ml) and morpholine (0.163 ml, 1.87 mmol) were added to a mixture (0.6 g) of phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 93; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (0.202 g, 0.447 mmol).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2][CH:3]([CH3:5])C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCC1C=C[CH:37]=[C:36]([Cl:40])[CH:35]=1>>[Cl:40][C:36]1[CH:35]=[C:2]([CH:3]=[CH:5][CH:37]=1)[CH2:1][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18]
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Reactant: Clc1cccc(CBr)c1
Agent: O=Cc1c(O)ccc2ccccc12
Product: O=Cc1c(OCc2cccc(Cl)c2)ccc2ccccc12

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C@H:3]([NH2:5])[CH3:4].C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[C:20](Cl)[N:19]2[N:32]=[CH:33][N:34]=[C:18]2[N:17]=1>ClCCl>[Cl:15][C:16]1[C:21]([C:22]2[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=2[F:28])=[C:20]([NH:5][C@@H:3]([C:2]([CH3:7])([CH3:6])[CH3:1])[CH3:4])[N:19]2[N:32]=[CH:33][N:34]=[C:18]2[N:17]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(C)(C)C
Yield: 76 %

Procedure:
With stirring, a mixture of 1.4 mmol of (R)-3,3-dimethylbut-2-ylamine, 1.4 mmol of triethylamine and 10 ml of dichloromethane was introduced into a mixture of 1.4 mmol of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-1,2,4-triazolo[1,5-a]-pyrimidine in 30 ml of dichloromethane. The reaction mixture was then stirred at room temperature for 16 hours and finally washed with 1 N hydrochloric acid and water. The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography. This gave the title compound in the form of colorless crystals in a yield of 76% (m.p.: 169-171° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.CCN(S(F)(F)[F:21])CC>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2([F:21])[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: N#Cc1cc(Cl)c(C2(O)COC2)cn1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(C2(F)COC2)cn1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
To a solution of 4-chloro-5-(3-hydroxyoxetan-3-yl)pyridine-2-carbonitrile (example 123b, 2.0 g, 9.5 mmol) in dry dichloromethane (50 ml) under an argon atmosphere cooled down to −75° C. was added DAST (1.61 g, 1.32 ml, 9.97 mmol). The reaction was stirred at −75° C. for 15 min, then let to warm up to 0° C. and stirred at 0° C. for 1 hour. The reaction was then quenched by addition of a 2M aqueous solution of sodium carbonate. The bi-phasic mixture was stirred at room temperature for 15 minutes, poured into a separatory funnel and extraction was carried out. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.81 g, 90%). MS (ESI, m/z): 213.0 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:11]1)=[O:9].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(OCC)(=O)C.C1COCC1.O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])=[CH:17][N:16]=2)[CH2:11]1)=[O:9]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(Nc1cnccn1)N1CC(Oc2ccc(Br)cn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cnccn1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a mixture of 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrazin-2-ylamide (Example 6 step 4; 100 mg, 0.285 mmol), 2-fluorophenylboronic acid (Aldrich, 60 mg, 0.428 mmol), potassium carbonate (118 mg, 0.86 mmol) and 1,1-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (23 mg, 10 mole %) in a microwave vial was added THF/H2O (10:1, 3 mL). Nitrogen gas was bubbled through the mixture for 5 mins and the vial sealed and heated at 100° C. in microwave synthesizer for 20 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and filtered through celite (2.5 g IST cartridge). A further 10 mL of ethyl acetate was washed through the celite pad and combined filtrate was washed sequentially with water (25 mL) then sat. sodium chloride solution (25 mL). Mixture was dried over sodium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a crude product, which was purified by flash chromatography, eluting with a gradient of 50 to 100% ethyl acetate in hexane to a afford a gummy solid. which was triturated with diethyl ether, filtered and dried to afford the title compound as colourless solid (67 mg, 64%)
Reaction SMILES: C([Mg]CCCC)CCC.C([Li])CCC.Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30].CN1CCOCC1.[CH:38]([CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:39]>O1CCCC1>[OH:39][CH:38]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]
Reactant: COCCCc1cn(C)c2ccc(Br)cc12
Reactant: CC(C)C(C=O)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCCc1cn(C)c2ccc(C(O)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 12.51 ml of dibutylmagnesium (1M in heptane) in 70 ml of tetrahydrofuran is cooled to 0° C. and admixed with 7.80 ml of n-butyllithium (1M in hexane). After 10 minutes, the mixture is admixed with a solution of 3.60 g of 5-bromo-3-(3-methoxypropyl)-1-methyl-1H-indole (residue 3) and 0.14 ml of N-methylmorpholine in 15 ml of tetrahydrofuran and stirred at 0° C. for 30 minutes. The reaction mixture is cooled to −78° C. and admixed with the solution of 3.02 g of tert-butyl 4-(2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine -3-carboxylate in 15 ml of tetrahydrofuran over 2 minutes. The resulting mixture is stirred at −78° C. for another 45 minutes and subsequently successively quenched with 1M ammonium chloride solution, diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are washed successively with 0.5N HCl (cold)(2×), water and brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound (diastereomer mixture) is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane). Rt=24.2/25.4 (gradient II).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br.Br[CH2:21][C:22]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[O:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:21][C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])[C@:10]([CH3:16])([C:12]([F:13])([F:14])[F:15])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)cn1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CN2c3nc(Cl)cc(=O)n3C[C@@]2(C)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.97 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are added to a suspension of 141.94 mg (5.91 mmol) of sodium hydride in 20 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 872.32 mg (2.96 mmol) of 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF is added dropwise to the reaction medium at 0° C. The reaction is stirred at room temperature overnight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 150 mg of (S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Cl.C(=O)([O-])O.[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(SCc3ccccn3)c2C#N)cc1
Reaction time: 2 h

Procedure:
9.28 g (30 mmol) of N-[4-(2-amino-3,5-dicyano-6-sulphanyl-4-pyridinyl)phenyl]-acetamide, 7.38 g (45 mmol) of 2-picolyl chloride hydrochloride and 10.08 g (120 mmol) of sodium hydrogen carbonate are stirred at room temperature in 100 ml of DMF. After 2 hours, 100 ml of water are added dropwise at from 40 to 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1>>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:19][C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:12][CH:11]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(Cl)s1
Product: CCOC(=O)c1ccc(NCc2ccc(Cl)s2)cc1

Procedure:
4-(((5-chloro-2-thienyl)methyl)amino)benzoic acid ethyl ester was prepared from ethyl p-aminobenzoate and 5-chloro-2-thiophenecarboxaldehyde. Melting point was 108°-109° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH2:30][NH:29][CH2:28][CH2:27][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:7][C:8]2[C:9]3[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CNCC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
N4-Cyclohexyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (93 mg, 0.23 mmol) was dissolved in methanol (3 mL). Acetic acid (0.013 mL, 0.23 mmol) was added followed by formaldehyde (0.017 mL, 0.23 mmol) and sodium cyanoborohydride (14.48 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude material was dissolved in few drops of methanol, filtered and purified by preparative HPLC (acidic system) yielding N4-cyclohexyl-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (15.00 mg, 15.59%). MS (ES+) m/z 418.2 (M+H)+
Reaction SMILES: C(O[CH:5]1[C:14]2[C:9](=[C:10]([O:18][CH3:19])[C:11]3[O:17][CH2:16][O:15][C:12]=3[CH:13]=2)[CH2:8][N:7]([CH3:20])[CH2:6]1)(=O)C>[C].[Pd].C(O)C>[CH3:19][O:18][C:10]1[C:11]2[O:17][CH2:16][O:15][C:12]=2[CH:13]=[C:14]2[C:9]=1[CH2:8][N:7]([CH3:20])[CH2:6][CH2:5]2
Reactant: COc1c2c(cc3c1OCO3)C(OC(C)=O)CN(C)C2
Agent: [Pd]
Solvent: CCO
Product: COc1c2c(cc3c1OCO3)CCN(C)C2
Yield: 85.9 %

Procedure:
0.28 g (1 mmol) of 4-acetoxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (9) was added to 4 ml of ethanol. This solution was then added with 100 mg of 5% palladium carbon and hydrogenated at room temperature. After the reaction was completed, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was added with 5 ml of water and made basic with an aqueous solution of sodium hydroxide. The resulted solution was extracted twice with 5 ml of methylene chloride and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.19 g of 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (13) as a crystal. Yield: 86%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccncc2)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccncc2)c1CO
Temperature: 5 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 5-methyl-3-pyridin-4-yl-isoxazole-4-carboxylic acid ethyl ester (7.1 g, 17.3 mmol) in THF (350 mL) was added at 5° C. lithium aluminum hydride (635 mg, 16.7 mmol). After stirring for 2 h at this temperature further lithium aluminum hydride (318 mg, 8.4 mmol) was added and stirred for 1 h at 5° C. Water (1.9 mL) was added carefully followed by aqueous sodium hydroxide (15%, 1.9 mL) and water (0.54 mL). The resulting suspension was stirred for 15 min at ambient temperature and filtered over Hyflo®. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (2.15 g, 65%) as a light yellow solid. MS: m/e=191.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[CH3:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(CC#N)cc1C
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)CCOC2CCCCO2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
6.6 g of 60% sodium hydride in oil are added portionwise at RT to a solution of 20 g of 3,4-dimethylphenylacetonitrile in 100 ml of anhydrous THF, and the mixture is left stirring at RT for 2 hours. 29 g of 1-bromo-2-(2-tetrahydropyranyloxy)ethane are then added dropwise and the mixture is left stirring at RT for 2 days. The reaction mixture is poured onto ice and extracted with EtOAc, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with toluene and then with a gradient of a toluene/EtOAc mixture from (99/1; v/v) to (90/10; v/v). 17 g of the expected product are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: COc1cccc(C=O)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 75.5 %

Procedure:
α-Aminomethyl-3,4-dimethoxybenzyl alcohol hydrochloride (5.84 g, 25 mmol) was suspended in methanol (30 ml). 2,3-Dimethoxybenzaldehyde (5 g, 30 mmol) was added to the suspension and then triethylamine (3.83 ml, 27.5 mmol) was added dropwise thereto under stirring at room temperature. The resultant solution was heated under reflux for 30 minutes and then sodium borohydride (1.4 g, 37 mmol) was slowly added thereto under stirring under cooling with ice. After the completion of foaming, the solvent was distilled off under reduced pressure. Water was added to the residue, which was made acidic with 3N hydrochloric acid and washed with ether. The cistern was made basic with aqueous ammonia and then subjected to extraction with dichloromethane. The dichloromethane layer was washed with water and then a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant crystals were washed with isopropyl ether to obtain 6.56 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:23][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][CH2:17]1)[CH2:12][CH2:11]3>O1CCCC1>[Br:1][C:2]#[C:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([OH:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C(Br)Br)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#CBr)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
A solution of 1,1-dibromo-2-[3α-(t-butyldiphenylsilyloxy)-5α-androstan-17β-yl]-ethylene (0.074 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with a 1M solution of (n-Bu)4N+F− (1.48 mL, 1.48 mmol) and the resulting solution was stirred at RT for 48 h. The mixture was quenched with saturated aqueous NH4Cl solution. Ethyl acetate was added and the organic layer was extracted with water and brine and was dried (Na2SO4). Evaporation of the solvent in vacuo followed by purification of the residue with flash column chromatography using methylene chloridelethyl acetate 95/5 as eluent afforded the desired compound named above.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][N:6]=1
Reactant: COc1cc(Br)cnc1OC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1cc(C#C[Si](C)(C)C)cnc1OC
Reaction time: 16 h
Yield: 70.6 %

Procedure:
Copper (I) iodide (0.56 g, 2.9 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.1 g, 2.9 mmol), and 5-bromo-2,3-dimethoxypyridine (12.8 g, 59 mmol) were added to triethylamine (80 ml) which produced a yellow suspension. The reaction was thoroughly degassed and ethynyltrimethylsilane (5.8 g, 59 mmol) was added to the stirred suspension which was then stirred for 16 hours and concentrated. The crude material was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) to afford 2,3-dimethoxy-5-[(trimethylsilyl)ethynyl]pyridine (9.8 g, 71%).