Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>>[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:21][C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[CH2:17][CH2:18]3)[C:6]=2[CH:5]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Agent: Cl
Product: N#Cc1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (282 mg, 75%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (333 mg, 0.98 mmol) and 3-(bromomethyl)benzonitrile (191 mg, 0.98 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.68 (s, 1H), 7.57 (d, 2H), 7.43 (t, 1H), 7.00 (s, 1H), 4.88 (d, 1H), 4.20 (m, 1H), 3.56 (s, 2H), 2.85 (d, 2H), 2.25 (dt, 2H), 2.12 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C19H19ClN5S, 384.1; Observed: 384.2 (M++1).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=2)[C:21]([OH:23])=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>CO>[CH3:1][O:22][C:21](=[O:23])[C:20]1[CH:24]=[C:16]([C:15]#[C:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:17]=[N:18][CH:19]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Add trimethylsilyl diazomethane (2.25 g, 19.7 mmol) to a cooled suspension of 5-phenylethynyl-nicotinic acid (2.0 g, 8.9 mmol) in 4:1 diethyl ether: methanol (30 mL) at 0° C. Warm to room temperature, stir for 2 h and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes, to give the title compound as a white solid (1.8 g, 85%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19](=[O:22])[CH2:20][SH:21])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl[C:27]1[C:28]([C:33]#[N:34])=[N:29][CH:30]=[CH:31][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:34][C:33]1[C:28]2[C:27](=[N:32][CH:31]=[CH:30][N:29]=2)[S:21][C:20]=1[C:19]([C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:23]=[CH:24][CH:25]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH3:18])=[O:22]
Reactant: N#Cc1nccnc1Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)c1sc2nccnc2c1N
Yield: 21 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetyl)-4-methylphenyl)benzamide 115 (0.094 mmol, 33 mg), 3-chloropyrazine-2-carbonitrile (0.094 mmol, 13 mg) and sodium carbonate (0.112 mmol, 12 mg) in ethanol (1 mL) was stirred 2 h at 50° C. Quenched in 1N HCl solution and extracted with CH2Cl2. Organic layer was dried and evaporated. Purification by HPLC gave N-(3-(7-aminothieno[2,3-b]pyrazine-6-carbonyl)-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 116 (9 mg, 21%). NMR (400 MHz, DMSO-d6) 1.74 (s, 6H), 2.27 (s, 3H), 7.37 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.81 (dd, J=8.2 Hz and 2.3 Hz), 7.95 (m, 2H), 8.04 (m, 3H), 8.82 (s, 2H), 10.44 (s, 1H). (m/z)=457 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][C@H:32]2[CH2:34][C@@H:29]1[CH2:30][N:31]2[C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][C@H:32]2[CH2:34][C@@H:29]1[CH2:30][N:31]2[C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]=3[N:9]=2)=[CH:41][CH:42]=1)=[O:36])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2C(=O)c1ccc(N)nc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5C[C@@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 25.5 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol, 1.0 eq) was combined with 5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (217 mg, 0.683 mmol, 1.0 eq) which gave 5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg) in 25% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.47 (br. s., 5H) 1.52 (br. s., 5H) 1.69-1.83 (m, 2H) 1.83-2.00 (m, 2H) 2.06-2.20 (m, 4H) 2.59 (br. s., 2H) 3.18 (s, 6H) 3.38-3.58 (m, 2H) 3.58-3.82 (m, 3H) 4.56 (br. s., 1H) 4.75-4.91 (m, 1H) 6.50 (s, 1H) 7.96 (br. s., 1H) 8.35 (br. s., 1H) 8.52 (br. s., 1H) 8.59 (br. s., 1H) 8.78 (s, 1H)
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:25]2[CH2:26][NH:27][CH2:28][CH2:29][N:24]2[CH2:23][CH2:22][OH:21])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: OCCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 0 °C
Yield: 43.7 %

Procedure:
To a solution of 5-bromo-5-decylbarbituric acid (0.619 g) in 1.3 ml of dimethylsulfoxide, kept under stirring at 0° C., a solution of 0.93 g of N-(2-hydroxyethyl)piperazine in 0.7 ml of dimethylsulfoxide is added dropwise, then the reaction mixture is stirred at room temperature for 1 hour. The mixture is then cooled to 0° C. and added with 30 ml of water. A white solid separates, which is kept under stirring for 1 hour, then is filtered and dried under vacuum at 50° C. 0.309 g of the product are obtained, m.p. 181-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br.CC(=O)OCC>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(O)ccc1Br
Yield: 84.5 %

Procedure:
To a solution of compound methyl 2-bromo-5-methoxybenzoate (100 g, 410 mmol) in DCM (2000 mL) was added and BBr3 (1N, 150 mL) at −78° C. under N2 The mixture was stirred at 0° C. under N2 for 24 hr. The reaction was quenched with MeOH (500 mL), concentrated to dryness, diluted with H2O (50 mL), and extracted with ethyl acetate (800 mL*3), The organic phase was washed with saturated sodium bicarbonate solution 50 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=1:1 to give title product (80 g, 85% yield) as yellow oil. LCMS (10-80 AB—2MIN.M): Rt=0.820, purity=85%, M+1=231.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1(C)C(C)=CC=CC=1>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(CCl)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -10 °C
Yield: 72.5 %

Procedure:
A solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 11.3 grams (0.1 mole) chloroacetyl chloride in 200 milliliters xylene was refluxed at about 140° C. for 20 hours. Upon cooling the reaction mixture to -10° C., 10.7 grams (73% yield) pure product precipitated; m.p. 146.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[O:31]=[C:32]1[N:36]([CH2:37][C:38]([OH:40])=[O:39])[C:35](=[O:41])[CH2:34][S:33]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:34]4/[C:35](=[O:41])[N:36]([CH2:37][C:38]([OH:40])=[O:39])[C:32](=[O:31])[S:33]/4)=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(c1)c(-c1ccc(F)cc1)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(-c2ccc(F)cc2)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-(4-fluorophenyl)-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-3-(4-fluorophenyl)-1H-indazole-5-carbaldehyde and (2,4-dioxothiazolidin-3-yl)acetic acid following General Procedure F.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14].[C:16]([CH2:24][C:25](=O)[CH3:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>C(O)C.C(O)=O>[C:16]([CH:24]=[C:25]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14])[CH3:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: CCOc1ccccc1OCC(O)CN
Reactant: CC(=O)CC(=O)c1cccnc1
Solvent: O=CO
Solvent: CCO
Product: CCOc1ccccc1OCC(O)CNC(C)=CC(=O)c1cccnc1
Temperature: 25 °C

Procedure:
4.2 g of (-)-1-amino-3-(o-ethoxyphenoxy)-propan-2-ol (laevo-rotatory) ##STR38## are dissolved in 30 ml of ethanol, 3.3 g of the nicotinoyl-acetone ##STR39## are then added and the mixture is heated for 4 hours under reflux, with addition of 1 drop of formic acid as the catalyst. The clear solution is cooled to room temperature and concentrated in a water pump vacuum. An oil is left, which solidifies after a short time. The solid product is recrystallised from toluene. (-)-1-(2-Nicotinoyl-1-methyl-vinylamino)-3-(o-ethoxyphenoxy)-propan-2-ol (laevo-rotatory) is thus obtained ##STR40##
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:14])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@@H](N)C(C)C)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](c3cccc(C(C)C)c3)C(C)C)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-isopropylphenyl)-2-methylpropan-1-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 573 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([CH2:42][C:43]#[N:44])[S:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:15]1[C:10]2[N:9]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[N:8]=[C:7]([C:37]3[CH:38]=[C:39]([CH2:42][C:43]#[N:44])[S:40][CH:41]=3)[C:11]=2[C:12]([O:17][CH3:18])=[N:13][CH:14]=1
Reactant: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(-c1csc(CC#N)c1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A mixture of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl)acetonitrile (84.0 mg) obtained in Step A of Example 93, tetrakis(triphenylphosphine)palladium(0) (13.0 mg) and 2M aqueous sodium carbonate solution (0.200 mL) in DMF (2 mL) was stirred under microwave irradiation at 130° C. for 1.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (70.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH:30]3[CH2:32][CH2:31]3)=[CH:24][C:23]=2[F:33])[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH:30]4[CH2:32][CH2:31]4)=[CH:24][C:23]=3[F:33])[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1
Yield: 83.4 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-106 by using N-(4-chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.300 g), KOH (0.300 g), water (2.0 mL), THF (10.0 mL) to afford 0.200 g of desired product. MS (m/z): 383.16 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:31]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[O:32])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C4CCC4)c3)nn12
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a solution of 7.0 g of methyl-6-(3-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 6 ml of N,N-diisopropylethylamine and 4.0 g of cyclobutane carboxylic acid chloride. This soltution was stirred for 4 hours, washed with 200 ml of saturated aqueous sodium bicarbonhate, dried and evaporated in vacuo. A small amount of dichloromethane was added and the mixture warmed to give 2.45 g of crystals. A second crop (3.5 g) was recovered from the mother liquor. Recrystallization from dichloromethane-hexane gave the desired compound as white crystals, mp 242°-245° C.
Reaction SMILES: O[N:2]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](OC=C)(=O)[CH3:18]>>[C:9]([N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)N(O)c1ccccc1
Reactant: C=COC(C)=O
Product: O=C(c1ccccc1)n1ccc2ccccc21

Procedure:
8.3 g of N-hydroxybenzanilide are heated with 125 ml of vinyl acetate and 250 mg of Li2PdCl4 for four and a half hours at 60° C. The reaction mixture is washed with brine, dried over magnesium sulfate, and concentrated by evaporation. The solid residue is shaken with diethyl ether, in the process of which a small amount of crystalline benzanilide precipitates. The organic phase is concentrated by evaporation, and chromatographed through silica gel (toluene/diethyl ether 1:1). As the first fraction are obtained 6.2 g of N-benzoylindole, m.p. 54°-55° C.; IR spectrum (CHCl3): 1710 (CO): NMR spectrum (100 MHz, CDCl3) 6.52 (d, J=4, CH); 7.1-7.7 (m, 9H); 8.38 (m, 1H) ppm.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (556 mg, 2.45 mmol, 1.0 eq) is added at room temperature to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.45 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by 1-hydroxybenzotriazole (421 mg, 2.69 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (550 mg, 2.81 mmol, 1.15 eq) and N,N-diisopropylethylamine (962 μL, 5.50 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0/9/1, v/v/v) to afford 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow solid (621 mg, 62% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH:14]1[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]1.[OH-].[Na+]>C(O)(C)C.O>[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OCCn1c(NC2CCNCC2)nc2ccccc21
Reaction time: 36 h

Procedure:
Combine (1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (5.0 mmol) and sodium hydroxide (2.0 g) in isopropanol (20 mL) and water (0.1 mL). Heat to reflux. After 36 hours, cool and evaporate the reaction mixture in vacuo to give a residue. Combine the residue and water. Extract the diluted residue three times with ethyl acetate. Combine the organic layers and extract with brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O.O>C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=CCCl
Solvent: CCO
Solvent: O
Product: Fc1ccc2nccn2c1

Procedure:
To a solution of 2-amino-5-fluoropyridine (10 g) in ethanol (200 mL), a solution of chloroacetaldehyde 50% in water (56 mL, 4.0 equiv.) was added. The reaction mixture was heated at reflux 2 Hrs, then was concentrated under reduced pressure to 100 mL. The residue was diluted in AcOEt (100 mL) and washed with a saturated aqueous solution of NaHCO3 (2*150 mL). The combined aqueous were saturated with NaHCO3 and extracted back with AcOEt (2*100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([C:25]5[O:24][CH:28]=[CH:27][CH:26]=5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1ccco1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccco4)nc3cc21

Procedure:
Furan-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-furoyl chloride (87 μl, 0.87 mmol). The title compound was obtained as brown powder (147 mg, 45%).
Reaction SMILES: C(O)(=O)C.CN(C)[CH:7]=[CH:8][CH:9]=O.[CH:12]([C:15]1[C:16]([NH2:21])=[N:17][NH:18][C:19]=1[NH2:20])([CH3:14])[CH3:13]>C(O)C>[CH:12]([C:15]1[C:16]([NH2:21])=[N:17][N:18]2[CH:9]=[CH:8][CH:7]=[N:20][C:19]=12)([CH3:14])[CH3:13]
Reactant: CN(C)C=CC=O
Reactant: CC(C)c1c(N)n[nH]c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1c(N)nn2cccnc12

Procedure:
Acetic acid (0.038 mL, 0.67 mmol) was added to a solution of 3-dimethylaminoacrylaldehyde (624 mg, 4.43 mmol) and the product from Example 112B (414 mg, 2.95 mmol) in ethanol (9 mL), and the reaction mixture was heated at 80° C. for 4 hours, then concentrated under vacuum to a dark oil. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc 50:50-0:100) to provide the title compound as a yellow solid. MS (ESI) m/z 177 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20]1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)=[CH:27][CH:28]=1
Reactant: O=C(O)C1c2ccccc2Sc2ccccc21
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1c2ccccc2Sc2ccccc21

Procedure:
9-Thioxanthenylcarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-9-thioxanthenylcarboxamide.