Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]([C:14]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+]>CO>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]([C:14]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH:17]([NH2:36])[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
200 mg (0.51 mmol) of the ketone (97) were dissolved in 1.5 mL of absolute methanol, then 390 mg (5.06 mmol) of ammonium acetate and 31.8 mg (0.51 mmol) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated, the residue dissolved in 50 mL of 1N aqueous sodium hydroxide and extracted twice with 100 mL of dichloromethane. The combined organic layer was dried over magnesium sulphate, filtered, and evaporated to give 150 mg of the title compound 98 in a purity sufficient to be used directly in the next step. Rt=1.18 min (Method 19). Detected mass: 397.3 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: COCCN
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: COCCNc1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(2-methoxy-ethyl-amino)-nicotinamide was prepared starting from intermediate E and 2-methoxyethylamine. MS calcd. for C25H23ClN4O3 [(M+H)+] 463.2, obsd. 463.0.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH:16]3[NH:18][CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:20]([BH3-])#N.[Na+]>C(#N)C.C=O.C(O)(=O)C>[NH3:10].[C:1]1([S:7]([N:10]2[CH2:11][CH:12]3[N:18]([CH3:20])[CH:16]([CH2:15][O:14][CH2:13]3)[CH2:17]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Product: N
Temperature: 23 °C
Reaction time: 2 h
Yield: 133.8 %

Procedure:
To a mixture of the above described 7-benzenesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (1.25 g, 4.658 mmol) in acetonitrile (40 ml) and 36.5% formaldehyde solution in water (0.53 ml, 6.987 mmol) and 5 drops of acetic acid at 23° C. was added sodium cyanoborohydride (1.464 g, 23.29 mmol) and the mixture was stirred at 23° C. for 2 h. Poured onto water and extracted twice with ethyl acetate, dried the organic layer over sodium sulfate, filtered off, evaporated all volatiles totally and dried in high vacuum to give after silica gel column chromatography with ethyl acetate and additional methanol and aqueous ammonia solution the title compound as a colorless oil (0.88 g, 67%), MS (ISP) m/e=283.1 [(M+H)+].
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[O:14]=[C:15]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:19]2[CH2:31][CH2:32][C:33](=[O:34])[C:18]=2[CH:17]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][C:36]=2[F:43])[NH:16]1.[CH:44]([N:47]([CH2:51]C)C(C)C)(C)C.CN>CN(C)C1C=CN=CC=1.C(#N)C>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([CH:17]2[N:16]([C:51]([NH:47][CH3:44])=[O:3])[C:15](=[O:14])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:19]3[CH2:31][CH2:32][C:33](=[O:34])[C:18]2=3)=[C:36]([F:43])[CH:37]=1)#[N:40]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)c(F)c1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1F
Temperature: 25 °C

Procedure:
4-Nitrophenyl chloroformate (23 mg, 0.11 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-fluorobenzonitrile (example 18, 43 mg, 0.10 mmol), N,N-diisopropylethylamine (70 μL, 0.41 mmol) and 4-dimethylaminopyridine (14 mg, 0.11 mmol) in acetonitrile (3.0 mL), and the mixture is stirred at room temperature over night. Another portion of 4-Nitrophenyl chloroformate (50 mg, 0.24 mmol) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) is added, and the mixture is stirred over night. Methylamine (2.0 M in tetrahydrofuran, 155 μL, 0.31 mmol) is added, and the mixture is stirred for 20 min at room temperature and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 27 mg; ESI mass spectrum [M+H]+=473; Retention time HPLC: 0.59 min (001_CA07).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([CH3:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:34].[ClH:36].[NH2:7][CH:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([CH3:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 416.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].N1C=CC=CC=1.[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45](Cl)=[O:46])[N:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([Cl:17])=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])=[O:46])[N:44]=1
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 20 °C
Reaction time: 66 h
Yield: 30.9 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulfonamide (780 mg, 1.632 mmol) was dissolved in DCM (32 ml) and pyridine (0.198 ml, 2.448 mmol) and cooled to 0° C. To this was added 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) dropwise. The reaction was left to warm up and after final addition was stirred for a further 66 h at 20° C. Reaction was incomplete so the mixture was cooled again to 0° C. and a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) was added dropwise. The reaction was left to warm up and was stirred for a further 23 h at 20° C. Reaction still incomplete so, the mixture was cooled again to 0° C. and a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) was added dropwise. The reaction was left to warm up and was stirred for a further 23 h at 20° C. The solution was treated with DCM (25 ml) and saturated aqueous sodium bicarbonate (25 ml) and stirred vigorously for 10 mins. The organic phase was then separated, washed with dilute aqueous sodium chloride (30 ml), passed through a hydrophobic frit, and loaded directly onto a 100 g silica cartridge. This was eluted with 0-100% ethyl acetate/cyclohexane over 60 mins using the Flashmaster II. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (321 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([NH2:23])=[C:16]3[N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]4[CH2:32][CH:33]([OH:41])[CH2:35]4)=[O:30])=[C:16]3[N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(Cl)c3)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(Cl)c3)nc12)N1CC(O)C1
Reaction time: 2 h
Yield: 74 %

Procedure:
To a DCM (0.7 mL) solution of (R)-5-(2-(3-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (20 mg, 0.06 mmol, prepared as described in the following paragraph), was added CDI (20 mg, 0.12 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (20 mg, 0.18 mmol) was added in one portion, followed by addition of DIEA (0.032 mL, 0.18 mmol). The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a solid (29 mg, 74% yield). MS (apci) m/z=431.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl.[OH-].[Na+].Cl>CCCCO>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:1][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[CH2:9][C:10]=2[CH:15]=1
Reactant: ClCCOCCOCCOCCCl
Reactant: Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Clc1ccc2c(c1)Cc1cc(Cl)ccc1OCCOCCOCCOCCO2
Yield: 23.1 %

Procedure:
10 g (0.037 mole) bis(2-hydroxy-5-chlorophenyl)-methane and 8.6 g (0.037 mole) 1,11-dichloro-3,6,9-trioxaundecane are dissolved in 100 ml n-BuOH. To this is added 6.5 g 50% aqueous sodium hydroxide. The resulting solution is heated to reflux for 15 hours, acidified with ethereal HCl, and solvent stripped in vacuo. The resulting gum is chromatographed on Neutral Alumina IV, eluting with ether/ethyl acetate. Appropriate fractions are collected, combined and recrystallized from methanol to yield 3.65 g white crystalline solid; m.p. 143.5°-144°. Yield: 23%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:20])[NH:12][C@H:13]1[CH2:17][C@@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([NH:12][C@@H:13]1[CH2:17][C@H:16]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]1)=[O:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C=C[C@@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.76 mL, 9.8 mmol) was added to a solution of cis-(4-hydroxymethyl-cyclopent-2-enyl)-carbamic acid tert-butyl ester (2 g, 9.4 mmol) and triethyl amine (1.96 mL,14.1 mmol) in CH2Cl2 (30 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. After filtration CH2Cl2 was added, and the organic phase was washed with 1M HCl, dried and concentrated under reduced pressure to yield of cis- methanesulfonic acid 4-tert-butoxycarbonylamino-cyclopent-2enylmethyl ester (2.64 g, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1ccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
To a solution of N-methylimidazole (10.0 g, 122 mmol) in acetonitrile (120 mL) was added benzoyl chloride (14.1 mL, 122 mmol) followed by triethylamine (17.0 mL, 122 mmol), while keeping the internal temperature at 5° C. The mixture was stirred 18 h at room temperature. After filtration, the filtrate was concentrated in vacuo, diluted with ethyl acetate (200 mL) and sequentially washed with sat. aq. sodium bicarbonate (150 mL), water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo.to afford (1-methyl-1H-imidazol-2-yl)(phenyl)methanone [21.0 g, yield 83%; HPLC/MS: m/z=187 (M+H); log P(HCOOH)=1.38].
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6]N(C)C)=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A thermostatically controllable reactor is charged with 553.8 g (2.1 mol) of (4-hydroxy-3,5-di-tert-butylbenzyl)dimethylamine und 450 g of petroleum ether 100/140. With stirring and blanketing with inert gas, the reaction mixture is heated to 60° C. and 366.4 g (2.2 mol) of triethyl phosphite are run into the clear solution. With cooling, 225.1 g (2.2 mol) of acetic anhydride are then added dropwise over 2 hours at 60° C., and stirring is continued for 1 hour at 60° C. The solvent is removed by distillation until the temperature is 115° C. The residual reaction solution is washed with 4×250 ml of water at 75° C. and dried by azeotropic distillation. Upon cooling to room temperature, the product crystallises and is filtered with suction, washed with petroleum ether 100/140 and dried, giving 693.2 g (92.6% of theory) of colourless diethyl 4-hydroxy-3,5-di-tert-butylbenzylphosphonate of m.p. 119°-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:21]#[N:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[CH2:52]([O:54][C:55](=[O:58])[CH:56]=[CH2:57])[CH3:53]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:21]([C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2/[CH:57]=[CH:56]/[C:55]([O:54][CH2:52][CH3:53])=[O:58])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 96 %

Procedure:
Tert-butyl 4-(2-bromophenyl)-4-cyanopiperidine-1-carboxylate (20, 100 mg, 0.28 mmol) and Pd(OAc)2 (7.0 mg, 0.030 mmol) were added to a vial, followed by tri(o-tolyl)phosphine (14 mg, 0.047 mmol). The reaction vial was purged with Ar (3×). Dry CH3CN (1.4 mL) and Et3N (103 μL, 0.74 mmol) were added, followed by ethylacrylate (36 μL, 0.33 mmol). The reaction mixture was heated at 85° C. overnight. The reaction was concentrated. Et2O (2 mL) was added to the mixture and was then filtered through Celite. The crude residue was purified by silica gel chromatography (gradient, 10% to 20% EtOAc/hexanes) to yield (E)-tert-butyl 4-cyano-4-(2-(3-ethoxy-3-oxoprop-1-enyl)phenyl)piperidine-1-carboxylate as a pale yellow oil (21, 102 mg, 96% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1H), 7.58 (dd, 1H), 7.41 (td, 1H), 7.38-7.34 (m, 1H), 6.31 (d, 1H), 4.29 (q, 1H), 3.29 (bt, 2H), 2.35-2.31 (m, 2H), 1.90 (dt, 2H), 1.47 (s, 9H), 1.35 (t, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH:13]=C)C(=O)OC(C)(C)C)[CH:2]=C.O=[O+][O-].[NH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=[CH:22][C:21]=2[CH2:20]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:18]1([C@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=[CH:22][C:21]=3[CH2:20]2)[CH2:13][CH2:12][NH:4][CH2:1][CH2:2]1
Reactant: N#Cc1ccc2c(c1)CC[C@H](N)C2
Reactant: C=CCN(CC=C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl diallylcarbamate (0.63 g, 3.2 mmol) in DCM at −78° C. was bubbled ozone until a blue color persisted. Nitrogen was bubbled through the reaction to remove excess ozone, followed by addition of a DCM solution of (6S)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.14 g, 0.80 mmol) and triethylamine (0.22 mL, 1.6 mmol). Then NaB(OAc)3H (0.85 g, 4.0 mmol) was added to the reaction. The mixture was allowed to warm to RT and stir overnight. LC showed formation of the desired product, which was separated by prep-TLC to furnish 87 mg of tert-butyl 4-[(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate. LC-MS (IE, m/z): 173 [M+1]+. The material was further treated with TFA to afford crude (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[C:10]([C:3]1[CH:4]=[N:5][N:6]([CH:7]([CH3:9])[CH3:8])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)#[N:11]
Reactant: CC(C)n1ncc(C#N)c1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncc(C#N)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of crude 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (0.72 g, 4.5 mmol maximum) and 4-nitrobenzoylchloride (1.3 g, 6.8 mmol) in dichloromethane (20 mL) was treated successively with triethylamine (1.8 mL, 14 mmol) and 4-N,N-dimethylaminoaniline (DMAP, 55 mg, 10 mol %). The mixture was heated to reflux (oil bath) for one hour and then allowed to cool to room temperature. The mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in pyridine (20 mL). Water was added, followed by concentrated aqueous ammonium hydroxide (5 mL). The reaction vessel was swirled manually and then left overnight at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with saturated aqueous sodium hydrogen carbonate solution and once each with 0.25 M aqueous hydrochloric acid and saturated aqueous sodium chloride solution. Drying over anhydrous magnesium sulfate was followed by filtration and then concentration under reduced pressure to provide N-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-4-nitrobenzamide as a dark yellow solid (1.3 g, 100%). MS (ES+): 299.6, 299.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:10]([I:11])=[CH:9]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1cnc2[nH]cc(I)c2c1
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21

Procedure:
1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 12 was prepared in 1 step from 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 2 and benzenesulfonyl chloride 11 as shown in Scheme 5.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[Se:6])([CH3:3])[CH3:2].Cl[CH2:12][C:13](Cl)=[O:14].N1C=CC=CC=1>O1CCCC1>[CH:1]([N:4]1[C:13](=[O:14])[CH2:12][Se:6][C:5]1=[N:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)NC(=[Se])NC(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)N=C1[Se]CC(=O)N1C(C)C
Yield: 101.1 %

Procedure:
0.42 g (2.0 mmol) of N,N′-diisopropyl selenourea were dissolved in 20 mL of tetrahydrofuran. 0.08 mL (1.0 mmol) of chloroacetyl chloride were added to the solution, and after stirring well, the mixture was allowed to react at 0 degrees Celsius for one hour. 0.09 mL (1.0 mmol) of pyridine was then added to the reaction mixture, followed by stirring at 0 degrees Celsius for additional 2 hours. The reaction mixture was extracted by an ordinary method, washed with water and dried, and the solvent was distilled off. As a result, 0.25 g of 3-isopropyl-2-isopropylimino-1,3-selenazolidin-4-one were obtained. The purity was 98.7%, and the yield was 100%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1>CO>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOCCn1ccc2c(Cl)ncnc21
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CCOCCOC)c1
Yield: 81 %

Procedure:
Following a procedure analogous to that described in Example 11, the title product was prepared in 81% yield from 4-chloro-7-[2-(2-methoxy-ethoxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and m-aminophenyl acetylene (1.2 eq) in methanol: MP: 240-241° C.; LC-MS: 336 (M+); anal. RPP18-HPLC RT: 4.29 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([N+:16]#[C-:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:18](=O)[CH3:19]>Cl(O)(=O)(=O)=O>[CH:10]1([NH:16][C:17]2[N:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]3=[N:1][C:18]=2[CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1cc(C)nc(N)c1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: CC=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1cc(C)n2c(NC3CCCCC3)c(C)nc2c1

Procedure:
Compound (19) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-4,6-dimethylpyridine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of acetaldehyde solution (0.3 M, DCM) and 10 μl of perchloric acid (w=20%).