Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:20])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.053 g, 0.194 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.110 g, 0.386 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 31 mg of yellow solid (42%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.91 (br s, 2H), 4.05-4.00 (m, 2H), 2.89-2.85 (m, 2H), 2.70-2.64 (m, 8H), 2.02-1.97 (m, 2H), 1.90-1.82 (m, 4H). MS (ESI): 383.2 (M+1). ESI-HRMS calculated for C21H27N4SO2 (MH+): 383.1900, Observed: 383.1895.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:14]([S:17][CH:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:20]([C:36](O)=[O:37])[CH2:19]1)(=[O:16])[CH3:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:14]([S:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([C:36](=[O:37])[NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[C:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:3]=2)[CH2:19]1)(=[O:16])[CH3:15]
Reactant: CC(=O)SC1CC(C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C=CCOC(=O)c1cccc(N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The above allyl 3-aminobenzoate (26.6 g, 0.15 M) was condensed with 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (55.2 g, 0.15 M) by suspension in toluene (750 ml) and addition of EEDQ (44.5 g, 0.18 M). The mixture was stirred overnight, diluted with EtOAc (2 l) and washed with dilute HCl, water and brine. The EtOAc phase was dried and evaporated, and the residue recrystallised from ethanol giving (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)-pyrrolidine (67.7 g). Nmr (DMSO-d6): δ 1.93 (quintet, 1H); 2.9 (m, 1H); 3.35 (m, 1H); 3.91-4.14 (m, 2H); 4.49 (quintet, 1H); 4.81 (dd, 2H); 5.22 (dd, 2H); 5.2-5.44 (m, 2H); 5.95-6.10 (m, 1H); 7.47 (d, 2H); 7.66 (t, 2H); 7.8-7.93 (m, 2H); 8.18-8.3 (m, 2H); 10.31 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[CH:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:14][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCC1
Reactant: CC(C)(CO)C(=O)O
Product: CC(C)(CO)C(=O)NC1CCCC1

Procedure:
Prepared as in Example 24a from hydroxypivalic acid and cyclopentyl amine as an orange oil (32%). 1H NR (400 MHz, DMSO-d6) δ 1.00 (s, 6H), 1.32-1.40 (m, 2H), 1.43-1.49 (m, 2H), 1.57-1.65 (m, 2H), 1.73-1.81 (m, 2H), 3.34 (d, J=4.0 Hz, 2H), 3.98 (m, 1H), 4.87 (t, J=4.0 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H). MS 186 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.11 g, 0.40 mmol) and 3-fluoro-5-piperidin-1-ylbenzoic acid (0.10 g, 0.40 mmol) according to conditions described in general procedures E and F. A light pink solid is produced (67 mg). Mp: 150-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.60 (bs, 6H), 2.49-2.57 (m, 4H), 2.89 (bs, 2H), 3.30 (bs, 4H), 3.61 (bs, 4H), 4.32 (bs, 2H), 3.96 (d, J=12.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.15 (d, J=9.3 Hz, 1H), 7.40-7.45 (m, 2H), 7.54-7.57 (m, 2H), 7.83-7.87 (m, 1H), 8.23 (s, 1H), 10.24 (s, 1H); MS 478 (M+1).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[N+:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:38]3[CH:39]=[CH:40][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc([N+](=O)[O-])cc4)nc32)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.9 mmol), 4-nitrophenylboronic acid (0.73 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (3 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with 1 M aqueous sodium hydroxide solution, once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was further purified by automated flash chromatography (methanol/dichloromethane) to provide tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate. MS (ES+): 536.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:22])=[C:4]([CH2:8][CH2:9][C@H:10]([OH:21])[C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Mn+3]>[Si:14]([O:13][C@@H:11]([CH3:12])[C@@H:10]([OH:21])[CH2:9][CH2:8][C:4]1[C:3]2[O:22][C:28]([C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc(N)c1O
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc2nc(-c3ccc(Cl)cc3)oc12
Yield: 76.3 %

Procedure:
A mixture of (3S,4S)-1-(3-amino-2-hydroxyphenyl)-4-(tert-butyldimethylsilyloxy)pentan-3-ol (P0016; 445 mg) and 4-chlorobenzaldehyde (192 mg) in toluene (15 ml) was refluxed for 2 hours. And then to the resulting mixture of the Schiffs base was added manganese triacetate (733 mg) and the reaction mixture was refluxed for 1 hour. The precipitated manganese diacetate was then separated by filtration and the solvent was removed under reduced pressure. The crude product was purified by silica gel (26 g) column chromatography eluting with hexane/ethyl acetate (20:1) to give (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-7-benzoxazolyl]pentan-3-ol (P0012; 465 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH3:24])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:38](OCCBr)(=[O:40])[CH3:39].CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:23]=2[CH3:24])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:39][CH2:38][OH:40])[CH2:11][CH2:10]1)#[N:2]
Reactant: CC(=O)OCCBr
Reactant: Cc1c(C(=O)Nc2ccc(N3CCCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
N-[3-Cyano-4-(homopiperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (1.5 g), potassium carbonate (0.6 g) and 2-bromoethyl acetate (0.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. To the residue were added 2N aqueous sodium hydroxide solution (10 ml) and ethanol (20 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure and dilute hydrochloric acid was added. The obtained crystals were recrystallized from hydrous ethanol to give the title compound (1.1 g), melting point: 124° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26].C(N(CC)CC)C.[Al]>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.[Cu]I>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Cc1c(I)cnn1-c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.119 mmol), 4-iodo-5-methyl-1-phenyl-1H-pyrazole (33.8 mg, 0.119 mmol), tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.012 mmol) and copper (I) iodide (6.79 mg, 0.036 mmol) were suspended in DMF (1 mL) and triethylamine (0.033 mL, 0.238 mmol) was added. The flask was wrapped with aluminum foil and sparged with nitrogen for 5 minutes. The reaction was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-methoxy-3-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [N+:1]([C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)([O-:3])=[O:2].[CH:9](O)=O>S(OC)(OC)(=O)=O>[CH3:9][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=[CH:7]1
Reactant: O=[N+]([O-])c1cnc[nH]1
Reactant: O=CO
Solvent: COS(=O)(=O)OC
Product: Cn1cncc1[N+](=O)[O-]
Yield: 82 %

Procedure:
202 parts of 5-nitroimidazole is dissolved in 600 parts of formic acid (90% by weight), 250 parts of dimethyl sulfate is added and the whole is heated for 6 hours. The formic acid is distilled off in vacuo. 420 parts of water is added to the residue, the whole cooled to from 0° to 5° C. and the unreacted 5-nitroimidazole (60 parts) is centrifuged off. The mixture is adjusted to pH 10 with aqueous ammonia solution (25% by weight) and the precipitate is separated at 0° to 5° C. 130 parts of 1-methyl-5-nitroimidazole having a melting point of 58° to 60° C. is obtained; this is equivalent to a yield of 82% of theory based on reacted 4(5)-nitroimidazole.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH:18]=O)=[C:11]2[C:15]([OH:17])=[O:16]>O>[NH2:5][CH:6]1[C:13](=[O:14])[N:12]2[C:11]([C:15]([OH:17])=[O:16])=[C:10]([CH:18]=[N:4][O:3][CH3:2])[CH2:9][S:8][C@H:7]12
Reactant: CON
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Agent: Cl
Solvent: O
Product: CON=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 8 h

Procedure:
A solution of 0.5 g of the hydrochloride of O-methylhydroxylamine in 10 ml of water is treated under stirring at 0° with 1.38 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid and stirred for ca. 8 hours at 0°. 7-Amino-3-[(methoxyimino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost white crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.Cl[C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:45]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OCC(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl) phenyl)urea (0.0867 g, 0.227 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added N,N-Diisopropylethylamine (0.1190 mL, 0.6832 mmol) followed by Isobutyl chloroformate (0.0442 mL, 0.341 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.52 (s, 2H), 3.86 (d, J=6.5, 2H), 3.77-3.68 (m, 4 H), 3.58 (s, 2H), 3.47 (d, J=4.3, 4H), 3.17-3.06 (m, 2H), 2.73-2.62 (m, 2H), 1.92 (dp, J=13.2, 6.6, 1H), 1.06 (t, J=7.2, 3H), 0.93 (d, J=6.7, 6H). LC/MS-m/z+483.3 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=[CH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[CH2:24][CH2:23]3)[C:12]3[C:13]([O:18][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[N:14][CH:15]=[CH:16][CH:17]=3)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH2:43][CH3:44]>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH:19]=[C:11]3[C:12]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[O:18][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH2:42][CH2:43][CH3:44])=[O:2])[C:9]=4[CH2:10]3)[CH2:23][CH2:24]2)=[CH:34][CH:33]=1
Reactant: O=C(O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 55 °C
Yield: 87.8 %

Procedure:
To a solution of the compound of Example 118 (109 mg, 0.22 mmol) in dry DMF (5 ml) was added potassium carbonate (91 mg) followed by propyl iodide (24 μL, 0.66 mmol). The mixture was heated to 55° C. for 14 hours. The mixture was diluted with ethyl acetate (200 ml), washed twice with water (200 ml) and then with brine (100 ml), and dried with sodium sulfate. The organic solvent was removed under reduced pressure and the residue subjected to silica gel chromatography using a dichloromethane:methanol gradient (0 to 5% MeOH over 1 hour) to give the title compound (103 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:24](=[O:25])[CH2:23][O:22][CH3:21])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (54 mg, 177 μmol) and 2-methoxyacetyl chloride (25 mg, 230 μmol) in DCM-pyridine (0.5 mL each) was stirred at rt. More 2-methoxyacetyl chloride (25 mg, 230 μmol) was added after overnight, resulting in a solution. The reaction was complete after 1 h. The mixture was concentrated, and diluted with NaHCO3 (saturated, 5 mL). After agitating for 30 min, the mixture was filtered, and washed with H2O (3×3 mL) to give a green solid (55 mg, 82%). LCMS: calc'd for C17H17ClN4O2S:376.0. found: 377.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.86 (s, 6H) 3.32 (s, 3H) 4.23 (s, 2H) 7.76-7.88 (m, 3H) 8.36 (s, 1H) 8.43 (s, 1H) 12.39 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](/[C:32](/[Cl:36])=[CH:33]/[CH2:34]Cl)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:12]3([CH2:13][CH2:14][N:15]([CH2:34]/[CH:33]=[C:32](/[C:29]4[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=4)\[Cl:36])[CH2:16][CH2:17]3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: ClC/C=C(\Cl)c1ccc(Cl)cc1
Reactant: O=C(c1ccnc(Cl)c1)N1CC2(CCNCC2)c2cc(Cl)ccc21
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCN(C/C=C(\Cl)c3ccc(Cl)cc3)CC2)c2cc(Cl)ccc21
Yield: 62.5 %

Procedure:
Alkylation of 1-(2-chloropyridin-4-yl)carbonyl-5-chloro-spiro[indolin-3,4′-piperidine] (0.18 g) with 1-chloro-4-((Z)-1,3-dichloro-propenyl)-benzene obtained in step 3 (0.11 g) was carried out following the procedure described in example 101, step 4 to afford 0.17 g of the title compound (64%) as a foam which was characterized by its mass and NMR spectra. MS (ES+) 548.
Reaction SMILES: [CH2:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)O)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)Br.Cl.[CH:39]1([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:39]1([NH:45][C:46]([CH:48]2[CH2:49][CH2:50][N:51]([CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=3)[CH2:1][CH3:2])[CH2:52][CH2:53]2)=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CCC(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1cccc([N+](=O)[O-])c1)N1CCC(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
A solution of α-ethyl-3-nitro-benzenemethanol (0.54 g, 2.98 mmol) in DCM (10 mL) is treated with PPh3 (1.6 g, 6.1 mmol).) and CBr4 (2 g, 6.03 mmol). The yellowish solution is stirred at RT for 2 h 30. Piperidine-4-carboxylic acid cyclohexylamide hydrochloride J-1 (0.82 g) is added at once, as well as DIPEA (2 mL). The RM is stirred at RT overnight then heated to 70° C. for 1H. The RM is evaporated under reduced pressure. The residue is partitioned between DCM (25 mL) and sat. aq. NaHCO3 (25 mL). The organic layer is washed twice with sat. aq. NaHCO3, dried over MgSO4 and evaporated under reduced pressure. The crude residue is purified by flash chromatography on silica gel using a gradient of DCM/MeOH/NH4OH 95:5:1 to 90:10:1. After concentration of the product-containing fractions, the title compound (0.173 g, 16%) is obtained as a colorless solid LC-MS A: tR=0.68 min; [M+H]+=374.21.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:16])[CH2:9][C@@H:8]3[CH2:25][O:26][CH2:27][CH2:28][N:7]3[C:6]=2[N:5]=1.CI.[CH3:31]COC(C)=O>CN(C=O)C>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:14][C:15]([N:17]([CH3:31])[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:16])[CH2:9][C@@H:8]3[CH2:25][O:26][CH2:27][CH2:28][N:7]3[C:6]=2[N:5]=1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Yield: 70.4 %

Procedure:
Sodium hydride (60% in oil) (12.57 mg, 0.314 mmol) was added to a suspension of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 100 mg, 0.262 mmol) in DMF (1 mL) at 0° C. The resultant mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.021 mL, 0.340 mmol) was added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 15 minutes. After addition of EtOAc, the resultant mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc to afford the title compound as a white solid (73 mg, 70.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.38 (m, 2 H), 1.48 (d, J=11.12 Hz, 2 H), 1.75-1.99 (m, 1 H), 2.80-3.01 (m, 4 H), 3.09-3.31 (m, 7 H), 3.40-3.64 (m, 2 H), 3.79-4.06 (m, 5 H), 4.17-4.27 (m, 1 H), 4.34-4.44 (m, 1 H), 7.12-7.29 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H26ClN5O3, 396.18; found 396.3.