Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Br[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12]>C(O)(C)C.ClCCl>[F:12][C:11]([F:14])([F:13])[C:10]1[N:7]=[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]2[CH:9]=1
Reactant: Nc1cnccn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: FC(F)(F)c1cn2ccncc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Pyrazinamine (11.89 g, 125 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Acros) was dissolved in isopropanol (IPA) (200 mL) and 3-bromo-1,1,1-trifluoro-2-propanone (12.98 mL, 125 mmol) was added. The solution was stirred at room temperature for 2 hours and the heated at reflux for 18 h. The solution was concentrated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (200 ml) and 20% IPA/DCM (300 ml). The aqueous phase was extracted with 20% IPA/DCM (5×200 ml) and the combined extracts were concentrated in vacuo. The residue was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid (17.69 g). The solid was dissolved in dichloromethane and initially purified by filtration through a plug of silica to afford product in 15.14 g. The solid was purified by flash chromatography (Biotage flash 65+, 0-100% [10% 2M NH3 in MeOH/DCM]/DCM) to afford the desired product in 5.61 g. LC/MS=408/410 (M+H)+, retention time=2.05 minutes (5 minute).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:5]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 2-chloronicotinoyl chloride (2.91 g, 16.6 mmol) in ethyl acetate (50 mL) was added to a mixture of 2-aminophenol (2.00 g, 18.3 mmol) and DIPEA (4.8 mL, 27.5 mmol) in ethyl acetate (50 mL) at 4° C. The reaction mixture was stirred for 1 hour. The organic mixture was washed with water and brine then concentrated under reduced pressure. The residue was dissolved in ethanol/THF 1:1 (75 mL) and 15% sodium hydroxide (25 mL) and the mixture was stirred at 50° C. for 45 min. The mixture was cooled down to room temperature and concentrated in vacuo to one third volume and then acidified to pH=2 with 3M HCl. The solid was filtered, washed with water and dried to afford title compound 13 (3.69 g, 81%) as a beige solid. LRMS (ESI): (calc) 248.04. (found) 249.2 (MH)+.
Reaction SMILES: B(F)(F)F.CCOCC.C(O[CH:13](OCC)[CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)C>C(Cl)Cl>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][C:21]2[CH:13]=[CH:14][S:15][C:16]=2[CH:17]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
To a solution of boron trifluoride etherate (14.45 mL, 115 mmol) in 2000 mL of methylene chloride stirring in a cold water bath 20° C. was added dropwise 1-(2,2-Diethoxy-ethylsulfanyl)-3-methoxy-benzene (28.2 gm, 110 mmol) dissolved in 500 mL of methylene chloride. The addition was complete in 3 hrs. and then the reaction was warmed to room temperature for a further 1.5 hrs. The reaction mixture was then quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was back extracted several times with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel (using a gravity column) using hexanes as the eluant to yield 10.9 gm of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1

Procedure:
A solution of 5.0 g (0.02 mol) of N-(4-bromophenyl)-α-chloroacetamide (Part A) and 5.05 mL (0.06 mol) of pyrrolidine in 100 mL of THF was stirred overnight at ambient temperature. The mixture was concentrated in vacuo and the residue was partitioned between H2O and EtOAc. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered, and evaporated in vacuo to afford 5.74 g of analytically pure title compound as crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li].O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Solvent: O
Product: CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.00 mL, 27.0 mmol, 1.00 equiv, Aldrich) in anhydrous ether at −78° C. under argon was added methyllithium (1.4 M in Et2O, 54.0 mL, 53.9 mmol, 2.00 equiv). Stirring was continued at −78° C. for 1.5 hours. Ether (200 mL) and water (40 mL) were added, and the two phases were separated. The aqueous solution was extracted with Et2O (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc to EtOAc-MeOH 9:1) to give 4.81 g (87%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].C(N(CC)C(C)C)C.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>ClCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Nitro-4-Chloro pyridine (10 mmol) dissolved in dichloromethane (25 mL) and diethyl iso propyl amine (20 mmol) followed Boc piperazine(10 mmol) was added to the above solution while cooling at 0° C. and the reaction mixture was stirred at room temperature for overnight . The dichloromethane was evaporated under vacuum. The resulting solid is extracted in to dichloromethane and washed with citric acid and brine solution. The evaporation of dichloromethane gave a yellow solid, 4-(3-Nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester which is used for next step without purification.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O.O>[Br:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:17][CH:16]=1
Reactant: OCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
tert-Butyldimethylchlorosilane (8.7 g) and imidazole (3.9 g) were added to a solution of 3-(4-bromophenoxy)propan-1-ol in N,N-dimethylformamide (193 mL) under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was ice-cooled and water and a saturated ammonium chloride solution were added, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1). Pyrrolidine (4.82 mL) and triethylamine (8.86 mL) were added to a solution of the resulting crude product in tetrahydrofuran (145 mL) under ice-cooling, and the mixture was stirred at room temperature for 27 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution was added, followed by extraction with a mixture of hexane-chloroform (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→80:1) to give the title compound (7.88 g, 79% (two steps)).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>O>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:21][NH:20][C:19]3[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Agent: Cl
Solvent: O
Product: CCc1ccc2c(c1)NC(=O)C2=NNc1ccc(S(N)(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared from 6-ethyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 79% yield: 1H NMR (DMSO-d6): δ1.16 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.74 (s, 1H), 6.89 (d, J=7.5 Hz, 1H), 7.22 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 11.02 (s, 1H), 12.70 (s, 1H); APCI−MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S.0.32 H2O: C, 54.88, H, 4.79; N, 16.00; S, 9.16. Found C, 54.81, H, 4.59; N, 16.06; S, 9.04.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:12][C:3]1[C:2]([CH3:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1c([N+](=O)[O-])ccc2cccnc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(N)ccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
7-Amino-8-methylguinoline. To a solution of 1.45 g of 8-methyl-7-nitroquinoline in 20 mL of ethanol are added 1.45 g of ammonium formate and a catalytic amount of 10% palladium-on-carbon. The resulting suspension is stirred at room temperature for 3 hours. The reaction mixture is filtered on Celite, with a methanol wash of the solids, and the filtrate is rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate/hexanes followed by recrystallization from hexanes/methylene chloride to provide 1.10 g of 7-amino-8-methylquinoline as a pale yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](Cl)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccco1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccco1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
43.5 g of N-hydroxyphthalimide were added to a solution of 31.1 g of furfuryl chloride in 80 ml of dimethylformamide, and the mixture was cooled to 0° C. 40.6 ml of triethylamine were then added dropwise to the mixture, after which the reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 24 hours. At the end of this time, the reaction mixture was poured into ice-water. The resulting colorless crystals were collected by filtration, to afford 53.1 g of N-furfuryloxyphthalimide, melting at 145-147° C.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1
Reactant: FC(F)(F)COc1ccc(CBr)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCc1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C
Yield: 54.6 %

Procedure:
Dissolve sodium azide (270 mg, 4.0 mmol) in DMF (30 mL). Cool the solution to 0° C., then add 2-bromomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (440 mg, 1.6 mmol) at 0° C. Slowly heat the mixture from 0° C. to 80° C. over 30 min. Cool the reaction, dilute with EtOAc (100 mL) and wash with 10% aqueous NaCl (3×25 mL). Collect the organic layer and concentrate in vacuo to a volume of 50 mL. Transfer the solution to a pressure vessel. Add 10% Pd/C (Degussa type E101, 50% water by wt, 500 mg) and pressurize the vessel under hydrogen (10 psi) for 1 h with stirring. Filter the mixture through Celite® and wash filter cake with warm methanol followed by DCM. Concentrate in vacuo, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (180 mg, 54%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[O:24]C)=[CH:5][CH:4]=1.[B].C(=O)=O.CC(C)=O.O>C(Cl)Cl>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[OH:24])=[CH:27][CH:28]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [B]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1NC(=O)C(Cc2ccc(O)c(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)S1
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a suspension of N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide (800 mg) in anhydrous methylene chloride (30 ml), a 1.0N boron tribromidemethylene chloride solution (2.20 ml) was slowly added dropwise in an argon atmosphere under cooling with dry ice-acetone and stirring. After stirred for 6 hours at room temperature, the reaction liquor was allowed to stand for 3 days. After water was added and the mixture was stirred for 30 minutes, this was concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water and then dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:methanol=40:1) to obtain 618 mg (80%) of aimed compound as crystals. These were recrystallized from ethanol-water to obtain purified aimed compound as a light brown powdery crystals. Melting point 146.0~148.0° C.
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[Li+].[CH3:17][N:18]([C:20]([N:23]([CH3:25])[CH3:24])(Cl)[Cl:21])[CH3:19]>C(#N)C>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[CH3:17][N:18]([C+:20]([N:23]([CH3:25])[CH3:24])[Cl:21])[CH3:19]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CN(C)[C+](Cl)N(C)C
Reaction time: 12 h

Procedure:
0.84 g (2.92 mmol) of lithium bis(trifluoromethanesulfonyl)imide in 4 ml of acetonitrile are added with stirring at room temperature to a solution of 0.5 g (2.92 mmol) of bis(dimethylamino)dichloromethane in 4 ml of acetonitrile. The mixture is stirred for 12 hours, and the solid LiCl is subsequently filtered off. Acetonitrile is distilled off. The crystals formed are dried at 50° C. under a reduced pressure of 10.0 Pa, giving 1.2 g of bis(dimethylamino)chlorocarbenium bis(trifluoromethanesulfonyl)imide, corresponding to a yield of 98.8%.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>C(Cl)(Cl)Cl>[C:5]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][CH:13]=1)(=[O:7])[CH3:6]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (26.0 g, 254 mmol) is slowly added dropwise to a solution of 4-isopropylaniline (17.2 g, 127 mmol) in 80 ml of chloroform. In the course of this, intense heating of the reaction mixture occurs. On completion of the dropwise addition, the mixture is stirred at room temperature for another 2 h. The reaction mixture is concentrated to dryness and the resulting, reddish-white solid is recrystallized from hexane.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH:17]=[CH2:18].C(Cl)(Cl)Cl>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCn1c2ccccc2c2ccccc21
Yield: 100 %

Procedure:
Carbazole (10.1 g, 0.057 mol) and potassium hydroxide (88% wt pellets, crushed, 7.1 g, 0.11 mol) were stirred in 100 mL DMSO at 50° C. for 30 min before dropwise addition of allyl bromide (14.7 g, 0.118 mol). After 15 min the reaction mixture was poured into a 500 mL separatory funnel containing 100 mL chloroform and washed 5 times with 200 mL water to give, after solvent evaporation at 60° C. under reduced pressure, compound 15 in >99% purity as a dark brown, viscous syrup which solidified upon cooling (11.9 g, 0.057 mol, 100% yield). 1H NMR (300 MHz, CDCl3): δ=8.14-8.06 (m, 2 carbazole H), 7.49-7.32 (m, 4 carbazole H), 7.28-7.19 (m, 2 carbazole H), 6.04-5.90 (m, CH═CH2), 5.19-5.10 (m, Z-HCH═CH), 5.07-4.97 (m, E-HCH═CH), 4.92-4.85 (m, NCH2). 13C NMR (300 MHz, CDCl3): δ=140.34, 132.27, 125.67, 122.90, 120.33, 119.00, 116.74, 108.74, 45.21.
Reaction SMILES: O[Li].O.C([O:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1)(=O)C.C1COCC1.[NH4+].[Cl-]>O>[OH:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
LiOH—H2O (6.58 g, 157 mmol) was added to a 0° C. solution of (5R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (23.6 g, 62.69 mmol) in 2:1 THF:H2O (320 mL). The reaction mixture was stirred for 10 minutes, and then warmed to room temperature. LC/MS looked the same at 3 hours and 4.5 hours. The reaction mixture was cooled to 0° C., and then saturated NH4Cl was added to the mixture. The mixture was stirred for 5 minutes, and most of the THF was removed by rotary evaporation. The mixture was extracted with EtOAc (3×250 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 65M: 4:1 DCM:ethyl acetate, then gradient to 1:1 to 1:4 DCM:ethyl acetate. Once the product was eluting, then ethyl acetate was flushed through the column. Then 30:1 DCM:MeOH eluted the rest of the product (8.83 g). The mixed fractions were re-flashed with Biotage 40M using the same conditions to give another portion (2.99 g), which gave a combined yield of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (11.82 g, 56.38% yield) as a foam. LC/MS (APCI+) m/z 335.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].P([O-])([O-])([O-])=[O:10].[K+].[K+].[K+]>>[C:1]([NH2:2])(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: N#Cc1cccnc1
Agent: [K+]
Product: NC(=O)c1cccnc1
Yield: 97.3 %

Procedure:
The reaction was carried out in a reaction mixture (30 ml), comprising 500 mM 3-cyanopyridine, 40 mM potassium phosphate buffer (pH 7.0) and resting cells (dry weight 2.3 mg). During the reaction, 3-cyanopyridine (500 mM) was added 7 times as soon as it was consumed. In this manner, 4.0 M 3-cyanopyridine was added in the course of 15 h and 3.89 M (475 g/l) nicotinamide was formed, corresponding to a yield of 97.3%. Nicotinic acid was not formed.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.C(Cl)Cl>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1ccc(OC2CCCCO2)cc1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
Into a 300 ml three neck flask were charged 25.4 g of 2,3-dihydropyran (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.), 41.4 g of p-hydroxybenzoic acid (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.), and 3.7 g of pyridinium p-toluenesulfonate (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.). The mixture was dissolved after addition of 20 ml of methylene chloride and 80 ml of absolute ether. After the mixture was vigorously stirred for about 3 hours, it was extracted 3 times with 70 ml of a 10% sodium hydroxide aqueous solution. The resulting extracted solution was neutralized with 1 N of hydrochloric acid until the pH is made to 6. The resulting precipitate was filtered and dried in a vacuum thereby obtaining 57.4 g of crude p-tetrahydropyranyloxy benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(Br)ccc1F
Product: Cc1cn(-c2ccc(Br)cc2C#N)cn1

Procedure:
This compound was prepared from 5-bromo-2-fluorobenzonitrile and 4-methylimidazole, as described in US2006/0004013.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].C(O)C.[OH-].[Na+]>O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCCCCS
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.46 %

Procedure:
A mixture of 200 g of 11-bromoundecanoic acid, 60 g of thiourea and 600 mL of absolute ethanol was stirred and heated at reflux for two hours. After heating was stopped a solution of 80 g of sodium hydroxide in 250 mL of water was then added dropwise. The mixture was held overnight and then heated at reflux for three hours. After cooling to room temperature a solid precipitated from solution. The reaction mixture was poured into a mixture of ice and 200 g of concentrated hydrochloric acid. The solids were filtered from solution then slurried with ice water, isolated by filtration and washed twice. The off-white solid was stored in a crystallizing dish for one week, then dried under vacuum (~1 mm of Hg) at about 45° C. The product was distilled under vacuum (~1 mm of Hg at ~160° C). NMR analysis indicated the desired product was obtained. The distilled product weighed 74.7 g representing 45.46% yield based upon the weight of starting 11-bromoundecanoic acid.