Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([NH:19][NH2:20])=[O:18])=[N:9]2)=[N:6][CH:7]=1.Br[C:22]1[CH:23]=CC(N2C(C(F)(F)F)=CC(C(OCC)=O)=N2)=N[CH:27]=1.O.NN.[CH2:45]([OH:47])[CH3:46]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:14])([F:16])[F:15])=[CH:11][C:10]([C:17]3[O:18][C:22]([CH3:23])([CH3:27])[N:20]([C:45](=[O:47])[CH3:46])[N:19]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CCO
Reactant: CCOC(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Reactant: NNC(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Agent: NN
Solvent: O
Product: CC(=O)N1N=C(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)OC1(C)C
Temperature: 100 °C
Yield: 95 %

Procedure:
Step-1: 1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide: A mixture of ethyl 1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (33 g, 91 mmol) and hydrazine hydrate (17.07 mL, 544 mmol) in ethanol (330 mL) was heated at 100° C. overnight. The reaction mixture was cooled back down to room temperature and the solvent was evaporated under vacuum. The residue was triturated with toluene to obtain 30 g (95%) of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H, D2O exchangeable), 8.72 (d, J=2.5 Hz, 1H), 8.40 (dd, J=2.5 & 8.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 4.58 (s, 2H, D2O exchangeable); ESI-MS (m/z) 350, 352 [(MH)+, Br79,81].
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6])(=O)[CH3:2].[NH:13]([CH:15](O)[CH3:16])[NH2:14].C[OH:19]>>[NH2:6][C:5]1[N:13]([CH2:15][CH2:16][OH:19])[N:14]=[C:1]([CH3:2])[C:4]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(O)NN
Reactant: CO
Reactant: CC(=O)C(C#N)c1ccccc1
Product: Cc1nn(CCO)c(N)c1-c1ccccc1

Procedure:
α-Acetylphenylacetonitrile (10 g) was dissolved in methanol (100 mL), and hydrazinoethanol (5.3 g) was added, and the mixture was heated under reflux for 4 hrs. After the completion of the reaction, the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform:methanol=40:1 was concentrated to give 5-amino-1-(2-hydroxyethyl)-3-methyl-4-phenylpyrazole (11.4 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:25])(=[O:21])[CH3:20]
Reactant: CNc1cccc(N)c1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzamide (3.6 g) in methylene chloride (100 ml) is added pyridine (4.8 ml), and thereto is added dropwise acetoxyacetyl chloride (3.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (4.2 g) having the following physical properties.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(C=O)c1OCc1ccccc1
Yield: 93 %

Procedure:
A mixture of 196.0 g (1.30 mole) of o-vanillin (Aldrich), 200 g of benzyl bromide (Aldrich), 500 g of anhydrous potassium carbonate and 1,500 mL of absolute ethanol is heated, with stirring, at reflux for 6 hours. After cooling, the supernatant is decanted and the remainder is filtered. The combined filtrate and supernatant is concentrated at reduced pressure to remove solvent. The remaining oil is extracted into 1 L of ether. The ether solution is washed with 500 mL of water, 600 mL of 1% potassium hydroxide solution, and 500 mL of water and then dried (potassium carbonate) and concentrated to give 263.4 g (84% yield) of product; mp 41-43° C. Reported top, 43° C. (Chem. Abstr. 62:16110a) .
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[O:20])[CH:14]=3)[C:9]2=[O:34])[CH2:6][CH2:5][C:4](=[O:35])[NH:3]1.Cl>C(Cl)Cl.C(OCC)C>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[O:20])[CH:14]=3)[C:9]2=[O:34])[CH2:6][CH2:5][C:4](=[O:35])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(N2Cc3cc(CNC(=O)N4CCNCC4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylcarbamoyl)piperazine-1-carboxylate (0.49 g, 1.0 mmol) in methylene chloride (100 mL) is treated with HCl (5 mL of a 2N solution in diethyl ether), and stirred at ambient temperature for 48 hours. The mixture is evaporated under vacuum, and triturated in ethyl acetate (10 mL), filtered, and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)(O)[O-:28].[Na+]>COCCOC.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][OH:28])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: O=C([O-])O
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(CO)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
A solution of 1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 20 ml 1,2-dimethoxyethane is stirred at room temperature for 3 hours with a solution of 0.47 g of sodium bicarbonate in 10 ml of water. The solvent is evaporated off under reduced pressure and the residue is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purifed by chromatography on a silica gel column using methylene chloride/ethyl acetate (2:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-hydroxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.35 ppm (d, 1H), 5.24 ppm (m, 1H), 4.59 ppm (d, 1H), 4.54 ppm (d, 1H), 3.50 ppm (s, 3H), 2.44 ppm (s, 3H), 2.34 ppm (s, approx. 1H, very broad), 1.36 ppm (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 90.1 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 4.5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.16 g (90%) of 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 212°-215°.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)C.O.[OH-].[Na+]>[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: c1ccc2c(c1)NCCN2
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCNc2ccccc21

Procedure:
A solution of 0.186 mole (25 g) of 1,2,3,4-tetrahydroquinoxaline is dissolved in 250 ml of ethanol and 17.6 ml of acetic anhydride is added dropwise with stirring. The solution is then diluted with 750 ml of water and basified with 1N sodium hydroxide. The solution is extracted with chloroform, the organic extracts are dried and then evaporated to provide the solid product, 1-acetyl-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=NCCc3c(C)cccc32)cc1
Agent: c1ccc(SSc2ccccc2)cc1
Product: COc1ccc(-c2nccc3c(C)cccc23)cc1

Procedure:
1-(4-Methoxyphenyl)-5-methyl-3,4-dihydroisoquinoline and diphenyl disulfide were reacted in the same way as in step (c) of Example 1 to afford 1-(4-methoxyphenyl)-5-methylisoquinoline as colorless needles having a melting point of 60.4° to 60.8° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@H:10]2[O:30][C@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[C@@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:11]2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CO>CN(C)C=O>[C:1]1([CH2:7][O:8][CH2:9][C@H:10]2[O:30][C@H:29]([C@@H:31]([CH2:33][O:34][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:32][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:11]2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@@H](O)[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(COC[C@@H](OCc2ccccc2)[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
An 850 mg portion of 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol was dissolved in dry dimethylformamide and added to a slurry of 218 mg of sodium hydride in dimethylformamide. After stirring 1 hour, 1.9 ml of benzyl bromide was added, the mixture stirred overnight, 5 ml to methanol added and the solvents evaporated. The residue was taken up in 50 ml of water and 50 ml of dichloromethane, the organic layer separated, washed with water and brine, dried and evaporated to an orange oil. This oil was flash chromatographed, eluting with hexane:ether (5:1). Evaporation of the fractions gave 1.06 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][OH:15].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCC(N)CO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCC(CO)Nc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-aminobutan-1-ol according to general procedure 1 providing the amino compound (70 mg, 18%) as yellow solid: Rf=0.53 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J=9.5 Hz, 1H), 7.48 (s, 1H), 6.45 (d, J=9.5 Hz, 1H), 4.51 (d, J=6.3 Hz, 1H), 3.97-3.90 (m, 2H), 3.75-3.72 (m, 1H), 2.65 (br, 1H), 1.76-1.64 (m, 2H), 1.04 (t, 3H); ES-MS: (M+H)=285, 287 m/z.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[N:18][OH:19])[NH2:17])=[C:5]2[CH2:4][O:3]1>C(OC(=O)C(C)C)(=O)C(C)C>[CH:8]([C:9]1[O:19][N:18]=[C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[O:3][CH2:4][C:5]=23)[N:17]=1)([CH3:2])[CH3:7]
Reactant: NC(=NO)c1ncn2c1COC(=O)c1ccccc1-2
Agent: CC(C)C(=O)OC(=O)C(C)C
Product: CC(C)c1nc(-c2ncn3c2COC(=O)c2ccccc2-3)no1
Yield: 112.8 %

Procedure:
5,6-Dihydro-6-oxo-4H-imidazo[1,5-a][4,1]benzoxazepine-3-amidoxime (2 g, 8 mmole) in isobutyric anhydride (6 ml) was heated at 150° C. for 1.5 hours. The crude product in ethyl acetate:hexane (1:1) was chromatographed on silica and then crystallised from ethyl acetate:hexane to give the product (1.4 g, 58%), m.p. 143°-144° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)O1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[CH3:34][C:30]1[N:29]([CH2:28][C:24]2[N:25]=[N:26][CH:27]=[C:22]([C:9]3[CH:18]=[C:17]([CH3:19])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)[CH:23]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc2ccccc12
Product: Cc1cc(-c2cnnc(Cn3ccnc3C)c2)cc2ccccc12
Product: Cl

Procedure:
The title compound, MS: m/e=351.8 (M+H+), was prepared from 4,4,5,5-tetramethyl-2-(4-methyl-naphthalen-2-yl)-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: CO.[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:8]=1[NH2:9].Cl.[C:24](=N)(OC)[CH3:25]>O>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:7]2[N:6]([CH2:5][CH2:4][OH:3])[C:24]([CH3:25])=[N:9][C:8]=2[CH:10]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCO
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCO
Yield: 42.6 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-hydroxyethyl)aminoanilin-5-yl)benzoxazole (see Working Example 88-1) (0.10 g, 0.4 mmol) was added methyl acetimidate hydrochloride (0.08 g, 0.7 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.05 g, 49% yield) as white crystals.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3([C:25]4[N:29]5[CH:30]=[C:31]([C:34]6[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=6)[CH:32]=[N:33][C:28]5=[N:27][CH:26]=4)[CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CO>[CH:43]1([NH:47][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([C:31]3[CH:32]=[N:33][C:28]4[N:29]([C:25]([C:22]5([C:18]6[CH:17]=[C:16]7[C:21](=[CH:20][CH:19]=6)[N:12]=[CH:13][CH:14]=[CH:15]7)[CH2:24][CH2:23]5)=[CH:26][N:27]=4)[CH:30]=3)=[CH:42][CH:41]=2)[CH2:46][CH2:45][CH2:44]1
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Reactant: NC1CCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC1)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.172 mmol) was added to a mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid dihydrochloride (18.5 mg, 0.0386 mmol), cyclobutanamine (4.12 mg, 0.0579 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (20.5 mg, 0.0463 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at RT for 3 h, and diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=460.1.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[N:7]=[C:8]([C:11]([NH2:13])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4]>CO>[Br:1][CH2:4][C:3]([C:6]1[N:7]=[C:8]([C:11]([NH2:13])=[O:12])[S:9][CH:10]=1)=[O:5]
Reactant: CC(=O)c1csc(C(N)=O)n1
Reactant: BrBr
Solvent: CO
Product: NC(=O)c1nc(C(=O)CBr)cs1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Bromine (1.3 g) was added slowly to a suspension of 4-acetylthiazole-2-carboxamide (1.3 g) in methanol (50 ml). The mixture was stirred for 3.5 hours at room temperature. The solvent was removed under reduced pressure to give 4-bromoacetylthiazole-2-carboxamide. The above residue and diaminomethylenethiourea (900 mg) were suspended in ethanol (50 ml) and the mixture was refluxed for 24 hours. The resulting precipitate was collected by filtration and suspended in water (50 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from methanol afforded 4-[2-(diaminomethyleneamino)thiazol-4-yl]thiazole-2-carboxamide (1.05 g).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Anhydrous K2CO3 (21.9 g, 0.159 mol) and methyl iodide (10.8 mL, 0.178 mol) were added to a solution of 2,5-dichlorophenol (23.5 g, 0.144 mol) in 215 mL acetone. The reaction was allowed to stir at room temperature for 20 hours, then filtered through a celite pad. The filtrate was concentrated to a residue which was taken up in diethylether. The ether solution was washed with 10% NaHSO3, water, several portions of 1 M NaOH, and brine, then dried with anhydrous Na2SO4. Upon filtration and concentration, the residue was distilled (8 mm Hg, 110° C.) to yield 23.7 g (93.5%) of a light yellow oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)[C:10](O)=[O:11].F[C:16](F)(F)C(O)=O.[CH:22]([C@:25]1([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:40]=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=3)[CH2:35][CH2:34]2)=[O:32])[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]1)([CH3:24])[CH3:23].C(N([CH2:54][CH3:55])CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:22]([C@:25]1([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:40]=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:44]=3)[CH2:35][CH2:34]2)=[O:32])[CH2:29][CH2:28][C@@H:27]([NH:30][CH:16]2[CH2:2][CH2:3][O:5][CH2:55][CH:54]2[O:11][CH3:10])[CH2:26]1)([CH3:24])[CH3:23]
Reactant: CCN(CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1yl}carbonyl)cyclopentanamine tris(trifluoroacetate) (25 mg, 0.034 mmol) , 3-methoxytetradyro4H-pyran-4one (13 mg, 0.10 mmol) and triethylamine (0.024 mL, 0.17 mmol) in methylene chloride (5 mL) was added sodium triacetoxyborohydride (22 mg, 0.10 mmol). The mixture was stirred under N2 at room temperature overnight and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9:1:0.5) to give 14 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give peak 1 (6.6 mg) and peak 2 (4.7 mg). LCMS calculated for C25H37F3N4O3: (M+1) 499; found 499.2 for both isomers.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CN
Product: CNc1ncccc1C#N
Temperature: 25 °C

Procedure:
A solution of 2-chloronicotinonitrile (97.82 g, 706 mmol) in 40% aqueous methylamine (706 ml) was heated to reflux for 1.5 hour. The excess methylamine was evaporated off and the resulting solids filtered and washed with water (250 mL). The crude product was dissolved in boiling water (1.4 1) and treated with charcoal and filtered through Celite. The aqueous filtrate was cooled to room temperature. After 10 hours the crystalline solid was collected, washed with water and dried to leave 71.10 g of 2-(methylamino)-nicotinonitrile (mp. 86-88 degrees C.). A sample was further purified by sublimation (100 degrees C. at 0.025 mm) mp. (87-88 degrees C.).
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[C:9](=[O:10])([O:8][C:1]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1)[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: Oc1ccc2cccnc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Oc1ccc2cccnc2c1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Di-tert-butyl dicarbonate (7.40 g, 33.92 mmol) and 4-(dimethylamino)pyridine (222 mg, 1.81 mmol) were added in sequence to 7-hydroxyquinoline (2.00 g, 13.75 mmol) in anhydrous N,N′-dimethylformamide (20.0 mL) at room temperature. After 18 hours, the reaction was diluted with EtOAc (250 mL). The organic layer was washed with 1.0 M NaOH (250 mL), water (3×250 mL), saturated aqueous NaCl solution (250 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 1:1 Hexanes:EtOAc) to give 28 as a colorless amorphous solid (3.26 g, 97%): 1H NMR (CDCl3, 500 MHz) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.17 (bd, J=8.4 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.43 (dd, J=8.8, 2.3 Hz, 1H), 7.40 (dd, J=8.3, 4.3 Hz, 1H), 1.60 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 151.7, 151.7, 148.9, 135.9, 129.0, 126.3, 122.0, 121.0, 120.2, 84.2, 27.8 (3C); IR (film) νmax 1759, 1277, 1240, 1142, 768, 750 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H15NO3, 246.1130. found, 246.1113.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16](Br)([C:22]([O:24]CC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(B([CH2:33][CH3:34])CC)C.O>C1C=CC=CC=1>[C:1]([C:9]1[N:10]2[C:15](=[CH:14][CH:13]=1)[C:16]([C:22]([O:24][CH2:33][CH3:34])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reactant: CCB(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole (436 mg, 1.0 mmol) in benzene (20 mL) was added triethylborane (1.0M in hexane, 5 mL, 5 mmol). The reaction mixture was stirred in an open vessel for one hour. Additional triethylborane (1 mL, 1 mmol) was added and the reaction was allowed to stir in an open vessel for an additional hour. The reaction mixture was poured into water and extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (85:15) to provide 266 mg (75%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate.