Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C@H:37]([CH3:40])[CH2:38][OH:39]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: C[C@@H](N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@H](C)CO)nc2n(C)c1=O
Yield: 61.9 %

Procedure:
Using general method E, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.085 g, 0.17 mmol) and (R)-2-aminopropan-1-ol (0.037 g, 0.50 mmol) were combined in THF (1 mL) to provide (R)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea as a white solid (0.055 g, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.0 Hz, 1H) 7.36 (s, 1H), 7.10 (d, J=12.4 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.10-4.06 (m, 1H), 3.56-3.53 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.17 (d, J=6.4 Hz, 3H); (ESI) m/z: 523.2 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:14]C=C)[CH:7]=[CH:6]2.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH2:24][CH:19]=[CH2:20])=[C:3]([OH:2])[CH:12]=[CH:11]2
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc2cc(OC)ccc2c1
Product: C=CCc1c(O)ccc2cc(OC)ccc12
Yield: 82 %

Procedure:
6-Methoxy-2-(2-propenyloxy)naphthalene (24.9 g, 116.2 mmol) was dissolved in N,N-dimethyl aniline (100 ml) followed by heating under reflux for 15 hours. After the organic solvent was distilled off under reduced pressure, 2N aqueous hydrochloric acid was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4), followed by recrystallization from ethyl acetate/hexane, to give 6-methoxy-1-(2-propenyl)-2-naphthol (20.3 g, Yield 82%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([N:28]([CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:34][CH2:35][O:36][CH:31]([CH2:30][N:28]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH3:29])[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN(Cc1ccccc1)CC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CN(Cc1ccccc1)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(N-benzyl-N-methylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(N-benzyl-N-methylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:9]=1[CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13]>N1C=CC=CC=1>[NH2:15][C:14]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[C:10]([C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]=2[Cl:7])[C:11]=1[C:12]#[N:13]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: Nc1nc[nH]n1
Solvent: c1ccncc1
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)nc2ncnn2c1N

Procedure:
A solution of 157 mg (1.87 mmol) of 3-amino-1,2,4-triazole and 417 mg (1.87 mmol) of (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) in 4.7 mL of anhydrous pyridine was stirred at reflux under air for 22 h and then cooled and concentrated in vacuo. The residue was partitioned between 5% aqueous citric acid solution and a 1:1 mixture of ethyl acetate and tetrahydrofuran. The organic phase was washed once more with the citric acid solution and then (after addition of some more tetrahydrofuran) with saturated aqueous sodium chloride solution. The combined aqueous fractions were re-extracted with a 2:3 mixture of ethyl acetate and tetrahydrofuran. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution with 2-3% methanol in dichloromethane) afforded the title compound as an amber-colored glass, which was used without further purification. LC-MS 305 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH3:21][O:22][NH2:23].Cl>N1C=CC=CC=1>[CH3:21][O:22][N:23]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:11]=[CH:10][N:9]=1
Reactant: CC#CCOc1cc(C(=O)c2ccccc2)ncn1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CC#CCOc1cc(C(=NOC)c2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 3 ml of pyridine were added 0.3 g of 6-(2-butynyloxy)-4-benzoylpyrimidine and 0.15 g of O-methylhydroxylamine hydrochloride, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into 10% hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give two isomers of (6-(2-butynyloxy)-4-pyrimidyl)phenylketone O-methyloxime (referred to as isomers A and B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>N1C=CC=CC=1>[C:17]([C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Compound 113 (250 mg, 0.80 mmol) was suspended in pyridine (1.5 mL). Decanoyl chloride (122 mg, 0.64 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (4 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (294 mg, 0.63 mmol, 98%) as a solid, mp 156-157° C.; 1H NMR (500 MHz, DMSO) δ 0.80 (3, t, J=7.0 Hz), 1.15-1.33 (21, m), 1.56 (2, t, J=7.0 Hz), 2.32 (3, t, J=7.0 Hz), 7.74 (2, d, J=8.0 Hz), 7.77 (2, d, J=8.0 Hz), 10.21 (1, s), 13.90 (1, s); 13C NMR (125 MHz, DMSO): δ 13.9, 22.1, 25.0, 28.6, 28.7, 28.8, 28.9, 29.3, 31.1, 36.0, 36.5, 118.6, 126.9, 135.7, 142.9, 167.0, 167.2, 171.9; MS (LCQ, ESI+) Calculated for C22H35N4O3S2 467.2. found 467.2 (M+H)+; HRMS (FAB+, m/z) Calculated for C22H35N4O3S2 467.2151. found 467.2131 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Yield: 98.9 %

Procedure:
2-Amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic-acid tert-butyl ester (7.96 g, 15.4 mmol) and hydrazine hydrate (3.85 g, 77.0 mmol) in ethanol (250 ml) was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the solid residue was extracted with diethyl ether (3×200 ml). The fractions were combined and the solvent removed in vacuo to give 5.9 g (100%) of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C>[Cl:31][CH2:30][CH2:29][CH2:28][N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([S:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[CH2:17]1
Reactant: ClCCCBr
Reactant: O=S(=O)(c1ccc2c(c1)CNCC2)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc2c(c1)CN(CCCCl)CC2)N1CCOCC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
1.2 g (4.4 mmol) of 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline and 1.0 g (10 mmol) of triethylamine were dissolved in DMF at 40° C., 1.1 g (6.6 mmol) of 1-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 40° C. for 3 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with methyl tert-butyl ether. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 2% methanol) to afford 0.7 g (2 mmol) of a pale oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)C4CC4)cc3CO1)CC2
Yield: 61.4 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (155 mg, 0.50 mmol, HPLC 0.776 min) and cyclopropanesulfonyl chloride (77 mg, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as a light brown solid (127 mg, 61%, HPLC 1.366 min), MS (ISP) m/e=414.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32]Cl)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1)#[N:21].C(N(C(C)C)CC)(C)C>C(O)C>[O:18]=[C:11]1[C:12]2([CH2:17][CH2:16][N:15]([CH2:32][C:31]3[N:27]([CH2:26][C:25]4[CH:34]=[CH:35][C:22]([C:20]#[N:21])=[CH:23][CH:24]=4)[CH:28]=[N:29][CH:30]=3)[CH2:14][CH2:13]2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:9][NH:10]1
Reactant: Cc1cccc(N2CNC(=O)C23CCNCC3)c1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CNC(=O)C23CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC3)c1

Procedure:
A solution of 1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one (0.25 g, 0.94 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (0.23 g, 0.94 mmol), and diisopropylethylamine (0.5 mL, 2.8 mmol) in absolute ethanol (5 mL) was heated under reflux overnight. The resulting mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 5% methanol in ethyl acetate. The appropriate fractions were collected and concentrated. The residue was triturated with diethyl ether, and the white solid precipitated was collected by filtration to provide the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]([F:44])([F:43])[C:26]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:27]=1[C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C:27]2[CH:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=[CH:38][C:26]=2[C:25]([F:24])([F:43])[F:44])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2C(F)(F)F)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester and (2,5-bistrifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[Br:39][CH2:12][C:10]1[CH:9]=[CH:8][C:4]2[B:5]([OH:7])[O:6][C:2]([CH3:13])([CH3:1])[C:3]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C(C)(C)OB2O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)OB(O)c2ccc(CBr)cc21
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of 3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (5.0 g, 28.4 mmol) in CCl4 (50 mL) at rt was added benzoyl peroxide (0.7 g, 2.8 mmol) following by NBS (5.0 g, 28.4 mmol). The reaction mixture was refluxed overnight, cooled to rt and treated with water. The aqueous layer was extracted with EA (20 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (4.5 g, yield 62%) as yellow oil. MS: 255 & 257 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][N:21](C(OCC5C=CC=CC=5)=O)[C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>C(O)C.Cl>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Yield: 71.5 %

Procedure:
A solution of phenylmethyl 4-[(6-fluoro-2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b]indol-2-yl)methyl]-5-methyl-1H-imidazole-1-carboxylate (100 mg) in ethanol (20 ml) and 2N hydrochloric acid (10 ml) was heated on a steam bath for 10 min. The cooled reaction mixture was then added to water (5 ml) and 2N sodium hydroxide (20 ml), and extracted with ethyl acetate (2×75 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (100:8:1) to give a solid which was triturated with ether to give the title compound (50 mg), m.p. 232°-233°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[OH-].[K+].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O>CO>[CH3:14][N:15]1[CH2:16][CH:17]=[C:18]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Yield: 97.6 %

Procedure:
5-Cyanoindole (Aldrich, 20.0 g) was added to a solution of KOH (22.4 g) in methanol (200 ml). N-Methyl-4-piperidone (Aldrich, 40.4 g) was then added dropwise and the resulting mixture refluxed for 4 hours, then cooled and poured into water. The resulting precipitate was filtered off and dried to give the desired product as a pale pink crystalline solid (32.6 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:3]=12.[CH3:15][NH:16][NH2:17].Cl>C(O)CC>[CH2:13]([C:12]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]3[CH:8]=[N:17][N:16]([CH3:15])[C:2]3=2)[NH:10][CH:11]=1)[CH3:14]
Reactant: CNN
Reactant: CCc1c[nH]c2ncc(C=O)c(Cl)c12
Agent: Cl
Solvent: CCCO
Product: CCc1c[nH]c2ncc3cnn(C)c3c12
Temperature: 85 °C
Yield: 64.5 %

Procedure:
4-Chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.76 g, 3.6 mmol) was suspended in n-PrOH (15 mL) then methylhydrazine (0.185 g, 4.01 mmol) was added. The mixture was heated at about 85° C. for about 20 min. The mixture was treated with concentrated aqueous HCl (0.330 mL, 4.01 mmol) then heated at about 110° C. for about 3.5 h. The solvent was evaporated under reduced pressure then the mixture was partitioned between water (20 mL) with aqueous HCl (5.0 N, 2 mL) and EtOAc (20 mL). The layers were separated then the aqueous layer was basified with saturated aqueous NaHCO3 and extracted with EtOAc (3×20 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 8-ethyl-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.465 g, 64%): LC/MS (Table 2, Method a) Rt=1.83 min; MS m/z 201 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:28])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:22]=3)[CH:19]=2)=[C:10]([C:29](O)=[O:30])[CH:9]=[N:8]1>>[N:23]1([C:21]2[N:22]=[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[CH:9][C:10]=4[C:29]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:30])=[O:28])=[CH:19][N:18]3[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1
Reactant: C1CCNC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using pyrrolidine and 1-Methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (46 mg, 58%). MS: m/z=409 (M+H+).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: N#Cc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In particular 2-cyano-benzothiazole 10 (0.84 mmol, 0.134 g) was suspended in 0.563 ml conc. H2SO4 at 0° C. 1.3 equivalents of concentrated HNO3 (1.1 mmol, 0.069 g) was added portionwise over 10 min to the stirring solution; not to exceed 0° C. over a total of ˜45 min. The reaction proceeded further for 2 h and at 5 h the product was evident. The reaction was then poured over ice/water, extracted into EtOAc, and concentrated in vacuo to yield a crude yellow residue 11. For analytical characterization, a small portion was purified by semi-preparative HPLC at 10 mL/min on a Waters preparative machine (Waters Symmetry prep C18, 7 μm, 19×300 mm column, photodiode array detection) with a linear gradient from 90% H2O (0.1% TFA) to 50% MeCN (0.1% TFA) for 30 min yielding a large product peak at ˜27 minutes. The fractions were collected and lyophilized using Kinetics Flexi-Dry freeze-dryer.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=1)[NH:9][N:8]=[CH:7]2.I[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH3:16][O:15][C:13]([C:11]1[CH:12]=[C:4]([O:3][C:2]([F:1])([F:17])[F:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:8]=[CH:7]2)=[O:14]
Reactant: COC(=O)c1cc(OC(F)(F)F)cc2cn[nH]c12
Reactant: CC(C)CI
Product: COC(=O)c1cc(OC(F)(F)F)cc2cnn(CC(C)C)c12
Yield: 56 %

Procedure:
Compound 13 was prepared following general method 1, using compound 8 as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 56%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH2:11].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][CH2:20][O:21][C:22](Cl)=[O:23]>O.C1(C)C(C)=CC=CC=1>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH:11][C:22]([O:21][CH2:20][CH2:19][Cl:18])=[O:23]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cccc(C)c1NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cccc(C)c1NNC(=O)OCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 17.7 g (0.1 mol) 2,6-dimethylphenylhydrazine hydrochloride, 21.2 g (0.2 mol) sodium carbonate in 50 ml water and 50 ml xylene are stirred for 30 minutes at room temperature, then cooled to 5°. 14.3 g (0.1 mol) chloroformic acid 2-chloroethylester is then added over a period of 1 hour, the temperature being maintained at 5°. The mixture is stirred at 5° for another hour, at the end of which 100 ml water are added, the precipitate thus formed filtered off, washed with water and dried. Further work-up as in Example 1b.