Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29].[Cl:41][CH2:42][C:43](Cl)=[O:44].C(N(CC)CC)C>O1CCCC1.O>[Cl:41][CH2:42][C:43]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])=[O:44]
Reactant: NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of (2S,4S)-2-aminomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (7.78 g) in a mixture of tetrahydrofuran (120 ml) and water (40 ml) was added dropwise chloroacetyl chloride (1.23 ml) with stirring under ice-cooling, keeping the pH 8-10 with triethylamine. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated in vacuo to remove the organic layer. The resulting residue was extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4S)-2-(chloroacetylamino)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (7.35 g).
Reaction SMILES: O[CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.N12CCCN=C1CCCCC2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.O>[N:39]([CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=[N+:40]=[N-:41]
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CN=[N+]=[N-])CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [1-(hydroxymethyl)cyclopropyl]carbamate (1 g, 5.3 mmol) in N,N-dimethylformamide (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture was stirred at 80° C. for 3 hours, another batch of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and the mixture was stirred at 80° C. for another 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were used for next step directly.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@@H:10]1[F:22])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C@@H:10]1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pd/C 10% (4.5 g) was added to a solution of (3S,4S) tert-butyl 4-(benzyl amino)-3-fluoropiperidine-1-carboxylate, 2.9 (19.1 g, 0.062 mol) in EtOH (500 mL). The reaction was stirred under hydrogen atmosphere (balloon pressure) for 16 hours at room temperature. After completion of reaction by TLC, the mixture was filtered through celite-bed and concentrated under reduced pressure to obtain the title compound (3S,4S) tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate, 2.11 (12.6 g, 93% yield). 1HNMR (CDCl3, 400 MHz): δ 4.33-4.14 (m, 1H), 4.13-4.02 (m, 2H), 2.94-2.78 (m, 3H), 1.89-1.86 (m, 1H), 1.48 (s, 9H), 1.42-1.34 (m, 1H); LCMS: 100%, m/z 163.1 (M−55, tert-But); HPLC: 99.17%, rt=5.146 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>CS(C)=O.CCOC(C)=O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][O:17][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: COCCOCOc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOCOc1cccc(COc2ccc3ccccc3n2)c1
Reaction time: 0.33 h

Procedure:
To a suspension of 60% NaH (44 mg, 1.1 mmol) in DMSO (2 mL) is added dropwise a solution of [3-(2-methoxy-ethoxymethoxy)-phenyl]-methanol (212 mg, 1.0 mmol, example 72) in DMSO (1 mL). Let stir 20 min. then added 2-chloroquinoline (180 mg, 1.1 mmol) and heated to 100° C. for 1 hr. Cooled reaction mixture to room temp. and diluted with EtOAc. The organic layer is washed with sat. NH4Cl soln., brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 25% ethyl acetate in hexanes) to give the title compound as a colorless oil. MS (ESI) 340 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][CH:7]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][CH:7]=1)=[S:14]
Reactant: CN=C=S
Reactant: NCCSCc1cncs1
Solvent: CCO
Product: CNC(=S)NCCSCc1cncs1

Procedure:
The reaction of 5-[(2-aminoethyl)thiomethyl]thiazole (2.24 g.) with methyl isothiocyanate (0.94 g.) in ethanol (10 ml.) gave a thiourea which was purified by chromatography on a column of silica gel with ethyl acetate as eluant. Recrystallisation from isopropyl acetate-methyl ethyl ketone-ether gave N-methyl-N'-]2-(5-thiazolylmethylthio)ethyl]thiourea (2.1 g.), m.p. 86°-88°. (Found: C, 38.6; H, 5.4; N, 16.9; S, 38.6. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[N:34][CH:33]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ncc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 27 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a pale orange solid (27% yield). M.p. 194-195° C., LCMS: m/z=472.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.38 (s, 3H), 2.51-2.58 (m, 4H), 3.31 (t, J=4.8 Hz, 2H), 3.49-3.58 (m, 2H), 3.89-3.97 (m, 4H), 4.51 (s, 2H), 4.95 (bs, 1H), 6.96 (s, 1H), 6.99-7.08 (m, 1H), 7.10-7.18 (m, 1H), 7.57 (s, 1H), 8.45 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]>C(O)CCC>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:20][C@@H:11]([C:8]4[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=4)[CH3:12])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: CCCCO
Product: CCOC(=O)c1ccc(-c2cc3c(N[C@H](C)c4ccccc4)ncnc3[nH]2)cc1
Temperature: 145 °C

Procedure:
1.8 g (6 mmol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) are suspended in 40 ml n-butanol and treated with 1.5 ml (12 mmol) (R)-phenethylamine. The mixture is heated to 145° C. under stirring. After 3 h a clear brown solution is obtained which is treated with a second portion of (R)-phenethylamine (0.75 ml, 6 mmol). After stirring for additional 2 h the reaction mixture is cooled in an ice bath and the title compound filtered and washed with cold n-butanol and ether; m.p. 288-290° C.; MS-ES+: (M+H)+=387.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:30][NH2:31]>CO>[F:22][C:17]1[CH:16]=[C:15](/[C:12](/[CH2:13][CH3:14])=[C:11](/[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)\[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:31][CH3:30])=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)c(F)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl) but-1-en-2-yl)-2-fluorophenol (310 mg, 0.75 mmol) in 10 mL MeOH was added 2 mL CH3NH2 (30% aq). The reaction mixture was heated at 85° C. for 13 h. and extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=10/1) to give the (Z)-product (39 mg, white solid) and (E)-product (14 mg, black brown crystal). m/z=408[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11][C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([S:11][C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[CH:3]=1
Reactant: Cn1ccnc1Sc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Cn1ccnc1Sc1cc(Cl)ccc1N
Reaction time: 18 h

Procedure:
A mixture of 3.0 g (10.7 mmoles) of the product from Example 49, 1.5 spatulas of Raney nickel and 200 ml of ethanol was hydrogenated at 1 atmosphere and room temperature for 18 hours. An additional spatula of Raney nickel was added and hydrogenation continued for 90 minutes. The mixture was filtered to remove the catalyst and the filtrates concentrated. The residue was recrystallized from dichloromethane/petroleum ether (bp 30°-60° C.) to give the product as colorless plates (1.7 g, 66%), mp 116°-120° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:25](#[N:30])/[CH:26]=[CH:27]/[C:28]#[N:29]>>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=3)=[C:27]([C:28]#[N:29])[C:26]=2[C:25]#[N:30])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCCCc1ccc(C=CC=C[C@H]2CC[C@H](CCC)CC2)cc1
Reactant: N#C/C=C/C#N
Product: CCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CCC)CC3)c(C#N)c2C#N)cc1

Procedure:
Using 1-(trans-4'-n-propylcyclohexyl)-4-(p-n-pentylphenyl)-1,3-butadiene and fumaronitrile, 3-(trans-4'-n-propylcyclohexyl)-6-(p-n-pentylphenyl)phthalonitrile was obtained by the same method as in Example 1. m.p. was 97° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.[H-].[Na+].CN(C)C=O.[CH2:35](I)[CH3:36]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=2)[CH2:35][CH3:36])[N:3]=1
Reactant: CCI
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(N(CC)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)amino]phenoxy}propionate (0.36 g), sodium hydride (0.05 g, 60%) and dimethylformamide (10 ml) was stirred at room temperature for 15 minutes. Ethyl iodide (0.17 g) was added and stirring was continued for a further 15 minutes. The mixture was then poured into ethyl acetate and washed with water, dried (MgSO4) and evaporated. Purification by column chromatography over silica gel gave ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-ethylamino]phenoxy}propionate as a yellow oil (0.40 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][CH:11]([CH3:18])[CH2:12]/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].[CH3:19][CH2:20][O:21][C:22]([CH2:24][N+:25]([O-:27])=[O:26])=[O:23].Cl>C(#N)C>[CH2:12]([CH:13]([CH2:14][C:15](=[O:17])[CH3:16])[CH:24]([N+:25]([O-:27])=[O:26])[C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH:11]([CH3:18])[CH3:10]
Reactant: CC(=O)/C=C/CC(C)C
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(C(CC(C)=O)CC(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylethylamine (7.9 mL) was added to the acetonitrile solution (50 mL) of (3E)-6-methylhept-3-en-2-one (6.25 g) and nitro ethyl acetate (5 mL) under argon gas atmosphere, and the reaction mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=95/5→75/25) to obtain the title compound (9.88 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][OH:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:27][OH:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCO)c2)c2ccc(F)cc21
Yield: 30.4 %

Procedure:
A solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.20 mg; 0.35 mmol), 2-bromoethanol (157 mg; 1.26 mmol) and K2CO3 (145 mg; 1.05 mmol) in MeCN (4 mL) was heated to 165° C. for 1 h in a microwave reactor. The reaction mixture was filtered and washed with MeCN. The combined filtrate was concentrated and purified by preparative TLC (petroleum ether/EtOAc=1/1) to afford 41 mg (30%) of the title compound as a yellow semi-solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(OC(=O)CC)(=O)CC.C([O:20][C@H:21]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([CH2:30][O:31][Si](C(C)(C)C)(C)C)[O:23][C@H:22]1[N:39]1[CH:47]=[N:46][C:45]2[C:40]1=[N:41][CH:42]=[N:43][C:44]=2[NH2:48])(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.N1C=CC=CC=1>[C:27]([O:26][C@@H:25]1[C@@H:24]([CH2:30][O:31][C:1](=[O:3])[CH3:2])[O:23][C@@H:22]([N:39]2[CH:47]=[N:46][C:45]3[C:40]2=[N:41][CH:42]=[N:43][C:44]=3[NH2:48])[C@H:21]1[OH:20])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21
Agent: CCC(=O)OC(=O)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H](O)[C@@H]1OC(C)=O

Procedure:
By substituting 9.5 ml. of acetic anhydride for the propionic anhydride in paragraph 1 (a) and using 200 ml. of dry pyridine, the product obtained by the procedure of paragraph 1 a) is 9-(2,3-di-O-acetyl-5O-(tert-butyldimethylsily)-β-D-arabinofuranosyl)adenine, which, on reaction with 31.3 g. of tetrabutylammonium fluoride in 300 ml. of tetrahydrofuran, following the procedure of paragraph 1 (b), gives 9-(3,5-di-O-acetyl-β-D-arabinofuranosyl)adenine. By substituting 23.4 ml. of butyryl chloride for the propionic anhydride in paragraph 1 (a) and using 17.9 g. of the silyl ether in 250 ml. of pyridine, the product obtained is 9-(2,3-di-O-butyryl-5-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl) adenine, which on reaction with 37 g. of tetrabutylammonium fluoride in 350 ml. of tetrahydrofuran following the procedure of paragraph 1 (b) gives 9-(3,5-di-O-butyryl-β-D-arabinofuranosyl)adenine.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:21][C:22]([F:33])([F:32])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[F:21][C:22]([F:32])([F:33])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:14][CH2:13][C:6]3([CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]3)[C:4]2=[O:5])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1(CCOC)CCNC(=O)C1
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Product: O=C1CC2(CCN1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared as a light brown solid (0.685 g) in analogy to example 1 step D) from 4-(2-methoxy-ethyl)-2-oxo-piperidine-4-carboxylic acid ethyl ester (1 g), dimethylaluminium chloride (1 M in hexane, 17.4 ml) and 4-(2,2,2-trifluoro-ethoxy)-phenylamine (1.25 g). MS (ESI): 343.12 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:7]CC)=O)C.[CH3:11][N:12]([C:14]([NH2:16])=[S:15])[NH2:13].C[O-].[Na+].CO>C(Cl)Cl>[CH3:11][N:12]1[C:14](=[S:15])[NH:16][C:4](=[O:3])[C:5](=[O:7])[NH:13]1
Reactant: CN(N)C(N)=S
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1[nH]c(=O)c(=O)[nH]c1=S
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
Under anhydrous condition, 35 g of diethyloxalate is added, dropwise, to a vigorously stirred solution of 21 g of 2-methyl-3-thiosemicarbazide, 32.4 g of fresh sodium methoxide, and 750 ml of methyl alcohol. The resulting suspension is heated at 60° C. for 4 hours, stirred overnight at room temperature, and heated at 70° C. for 15 hours. The white suspension is cooled to room temperature, 200 ml of ice water is added and the reaction concentrated in vacuo. The residue is cooled to 0° C. and made acidic with 2N hydrochloric acid. The reaction mixture is concentrated, ethyl alcohol is added and the suspension is heated to boiling. The white precipitate is collected, washed with hexane and dried to give 11 g of the crude product. Eight grams of the crude product is heated in methylene chloride and filtered while hot. The collected solid is resuspended in methyl alcohol and a solution of 4N potassium-2-ethyl hexanoate is added. The mixture is cooled to 0° C. and the precipitate collected. The solid is dissolved in water, filtered, and 2N hydrochloric acid is added to the clear 0° C. solution. The resulting precipitate is collected and dried to give 4.1 g of the pure product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH2:20]>C1(C)C=CC=CC=1.C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][NH:20][CH3:19])[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CNCc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (2.0 g) in 50 mL toluene and 50 mL THF was added 20 mL of 40% methylamine in H2O. The reaction mixture was stirred at room temp under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL MeOH and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temp under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g (2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-N-methylmethanamine (53% yield). MS (Q1) 300 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[O:5][C:4]2[C:12]([C:15]([O:17]C)=[O:16])=[CH:13][S:14][C:3]1=2.Cl>O1CCOCC1>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[O:5][C:4]2[C:12]([C:15]([OH:17])=[O:16])=[CH:13][S:14][C:3]1=2
Reactant: COC(=O)c1csc2c(=O)cc(C(F)(F)F)oc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1csc2c(=O)cc(C(F)(F)F)oc12
Temperature: 22.5 °C
Yield: 69.2 %

Procedure:
A mixture of 0.70 g of Compound 4A, 5.6 mL of dioxane and 8.4 mL of 9N hydrochloric acid was stirred at reflux for 75 minutes. After cooling to 20-25° C., the precipitated solid was filtered, washed with dioxane/water 1:1.5 and water to afford 0.46 g of the title compound as a grey solid melting at 249-251° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Nc2ccnc3[nH]c4c(c23)CNCC4)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4cccc(F)c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
(3-Fluoro-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (15 mg, 0.05 mmol), acetic anhydride (53 μL, 0.05 mmol), and triethylamine (22 μL, 0.16 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 61 (3 mg, 15% yield) as an oily residue. LC-MS (M+H=325, obsd.=325).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](I)[CH:13]=1>C(N(CC)CC)C.C(#N)C.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>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: Brc1cncc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cncc(Br)c1
Reaction time: 16 h
Yield: 99 %

Procedure:
Add trimethylsilylacetylene (54.6 mL, 389.4 mmol) to a stirred mixture of 3-bromo-5-iodopyridine (100 g, 354 mmol) in triethylamine (800 mL) and acetonitrile (800 mL). Purge the system with nitrogen and add bis(triphenylphosphine)palladium(II) dichloride (3.54 mmol, 2.48 g) and stir for 16 h. Concentrate and suspend the residue in 1800 mL of hexanes. Stir for 2 h, filter and concentrate to give the title compound as a brown solid (92g, 99%).