Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:27]([O:31][C:32](=[O:46])[C@H:33]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:27]([O:31][C:32](=[O:46])[C@H:33]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[NH:34][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc2ccccc12
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 61 mg of N-(1-diethoxyphosphoryl-3-phenylpropyl) -leucine and 39 mg of 3-(α-naphthyl) -L-alanine tert-butyl ester in 1.0 ml of dichloromethane was cooled to 0° C. Then 26 mg of 1-hydroxybenzotriazole monohydrate and 34 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added to the solution which was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with 15 ml of dichloromethane, and the diluted solution was washed with 15 ml of a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography (hexane: ethyl acetate=1:1) to yield the title compound as two mixtures each of which are composed of two stereoisomers (42 mg of a/b mixture, 35 mg of c/d/mixture). (iv) N-[N-(3-phenylphosphonopropyl)leucyl]-3-(α-naphthyl)-L-alanine
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([CH:14]=1)[CH:12]=O.[C:21]([OH:33])(=[O:32])[CH2:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(OC(=O)C)(=O)C>C(O)C>[C:26]1([C:24]2[O:33][C:21](=[O:32])[C:22](=[CH:12][C:11]3[CH:14]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=3[S:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[N:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cc(Cl)ccc1Sc1cccs1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2)=NC1=Cc1cc(Cl)ccc1Sc1cccs1
Reaction time: 2 h

Procedure:
8.4 g (0.1 mole) of sodium bicarbonate is added, with stirring, to the mixture of 25.5 g (0.1 mole) of 5-chloro-2-(2-thienylthio)-benzaldehyde and 17.9 g (0.1 mole) of hippuric acid in 34.7 g (0.34 mole) of acetic anhydride, and the reaction mixture is stirred at 90°-95° for two hours. It is thereupon cooled to 25°; to the thick crystal mass is added 300 ml of 50% ethanol, the solid substance is filtered off with suction and is washed with 150 ml of 50% ethanol. Drying in a vacuum chamber leaves 2-phenyl-4-[5-chloro-2-(2-thienylthio)-benzylidene]-2-oxazolin-5-one in the form of yellow crystals, m.p. 125°-127°.
Reaction SMILES: COC(C1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[C:18]([O:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:7]C1)=O.[O:33]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1.[CH3:58][N:59](C=O)C>>[Cl:32][C:26]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=1[O:24][C:18]1[C:17]([C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:59]([CH2:38][C:35]3[CH:36]=[CH:37][O:33][CH:34]=3)[CH2:58][CH2:7]2)=[O:16])=[CH:22][C:21]([F:23])=[CH:20][N:19]=1
Reactant: COC(=O)C1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Reactant: CN(C)C=O
Reactant: O=Cc1ccoc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCN(Cc2ccoc2)c2ccccc21
Temperature: 150 °C
Yield: 18 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (25.1 mg, 0.06 mmol, 1.0 equiv; Example 148) in anhydrous DMF (1 mL) was added furan-3-carbaldehyde (23.1 mg, 20 μL, 0.24 mmol, 4.0 equiv; [CAS RN 498-60-2]), dibutyltin dichloride (1.8 mg, 0.006 mmol, 0.1 equiv; [CAS RN 683-18-1]) and phenylsilane (13.0 mg, 15 μL, 0.12 mmol, 2.0 equiv; [CAS RN 694-53-1]). The reaction mixture was heated by microwave irradiation to 150° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 5.4 mg (18%) of the title compound as a light yellow solid. MS (ISP): 498.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C[O-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([OH:27])=[C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)[CH:17]=1.C(O)C>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([OH:27])=[C:16]([C:18](=[N:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:17]=1
Reactant: NCCCC(=O)O
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1cc(Cl)cc(C(=NCCCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
4-Aminobutanoic acid (2.2 g; 0.0213 mol), sodium methoxide (1.16 g; 0.0213 mol) and (5-chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methanone (6 g; 0.0213 mol) are introduced into a mixture of 200 ml of ethanol and 400 ml of methanol, and the resulting mixture is then evaporated to dryness. Ethanol (500 ml) is added to the residue and the mixture is then evaporated to dryness. The latter operation is repeated 4 times. The residue is dissolved in 1 liter of water and the pH is acidified to pH 4 by the addition of citric acid. The precipitate is filtered off, washed with water and then dissolved in CH2Cl2. The organic solution is washed with water, dried (MgSO4) and filtered, and the filtrate is evaporated to give an oil, which is crystallised once from petroleum ether and recrystallised twice from AcOEt.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].C1COCC1.[OH-].[Na+]>CO>[CH2:22]([N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1sccc1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccsc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.8 %

Procedure:
To a mixture of 1.494 g (3.583 mmol) of the product of Example 5 dissolved in 15 mL of methanol and 15 mL of THF was added 15 mL of 1N NaOH solution. The reaction mixture was stirred at room temperature for 36 h and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 1.327 g (92%) of the desired carboxylic acid as a white solid. CI Mass Spec: 404 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1>[Pd].CO>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1
Reactant: CN(C)CCOc1cnc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1cnc(N)cn1
Reaction time: 2 h
Yield: 90 %

Procedure:
In a 500 mL round bottomed flask containing N,N-dimethyl-2-(5-nitropyrazin-2-yloxy)ethanamine (270 mg, 1.27 mmol, Eq: 1.00) was added MeOH (20 ml) and 10% Pd/C (60 mg). The reaction was stirred under a hydrogen atmosphere for 2 hrs then stored at 0° C. for 3 days. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo to afford 209 mg, (90%) of the title compound as a gummy solid.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[CH:35]=[CH:34][C:18]4[O:19]C(C5C=CC=CC=5)(C5C=CC=CC=5)[O:21][C:17]=4[CH:16]=3)=[O:14])[N:10]=[C:6]2[N:5]=[C:4]([CH3:36])[CH:3]=1>FC(F)(F)C(O)=O.O>[OH:21][C:17]1[CH:16]=[C:15]([CH:35]=[CH:34][C:18]=1[OH:19])[C:13]([NH:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:36])[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=1)=[O:14]
Reactant: Cc1cc(S)n2nc(CNC(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(S)n2nc(CNC(=O)c3ccc(O)c(O)c3)nc2n1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
N-[(7-Mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidin-2-yl)methyl]-2,2-diphenyl-1,3-benzodioxol-5-carboxamide (22.7 g) are stirred for 1 hour in 210 ml of trifluoroacetic acid and 5 ml of water. A small amount of insoluble material is filtered off and the mother liquor is evaporated to dryness. The yellow residue is treated with 900 ml of ethyl acetate, stirred in an ultrasound bath for 1 hour and subsequently cooled in an ice bath. The yellow solid is filtered off and dried in a vacuum at 40° C. There are obtained 14.4 g of 3,4-dihydroxy-N-(7-mercapto-5-methyl[1.2.4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-benzamide as a yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:19][C:20]([O:22]CC)=[O:21])[C:11](=[O:18])[C:12]([CH:15]([CH3:17])[CH3:16])([CH3:14])[N:13]=2)=[N:7][CH:8]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:19][C:20]([OH:22])=[O:21])[C:11](=[O:18])[C:12]([CH:15]([CH3:17])[CH3:16])([CH3:14])[N:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(C)(C(C)C)N=C1c1ccc(CC)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccc(C2=NC(C)(C(C)C)C(=O)N2CC(=O)O)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of ethyl 2-(5-ethyl-2-pyridyl)-4-isopropyl-4-methyl-5-oxo-2-imidazoline-1-acetate (2.12 g, 6.41 mmol) in tetrahydrofuran is treated with 2N sodium hydroxide (8 mL). The resulting mixture is stirred at room temperature for 16 hours. After this period, the reaction mixture is concentrated in vacuo to obtain a residue. The residue is acidified with concentrated hydrochloric acid and then extracted with ether. The organic extract is dried over magnesium sulfate, vacuum filtered through diatomaceous earth and concentrated in vacuo to give the title product as a white solid, mp 134°-136° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@@H:22]1[CH2:34][OH:35])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23][C@@H:22]1[CH:34]=[O:35])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)[C@@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)[C@@H](C=O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To a stirring solution of anhydrous DMSO (1.8 mL, 25.36 mMol) in CH2Cl2 (40 mL) at −78° C. was added oxalyl chloride (2 mL, 23.78 mMol) slowly. After 20 min, a sample of (3R,4S)-tert-butyl 4-(benzyloxycarbonyl)-3-(hydroxymethyl)piperidine-1-carboxylate (5.78 g, 15.85 mMol) dissolved in CH2Cl2 (30 mL) was added to the reaction slowly. Stirring was continued for 1 h. Triethylamine (6.6 mL, 47.55 mMol) was added dropwise. Stirring was then continued with a gradual warm up to 0° C. over 1 h. Partitioned the mixture between water and CH2Cl2. Aqueous layer was re-extracted with CH2Cl2. Combined organic layer was washed with brine and dried (Na2SO4). Filtered, concentrated and chromatographed to get the desired product, (3R,4S)-tert-butyl 4-(benzyloxycarbonyl)-3-formylpiperidine-1-carboxylate as a pale oil (3.8 g, yield=67%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(Cl)Cl>CO>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[C:7]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: COc1ccccc1C=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (1.05 g, 5 mmol) and 2-methoxybenzaldehyde (0.816 g, 6 mmol) in 20 mL of methanol was added KF—Al2O3 (0.75 g, 4.5 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was recrystallized from alcohol and CH2Cl2 to give 1.2 g of CYD-1-70 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 8.84 (s, 0.36H), 8.26 (m, 1.65H), 8.10 (m, 3.05H), 8.02 (s, 0.57H), 7.55 (m, 4H), 7.24 (m, 1.24H), 7.10 (m, 0.91H), 3.84 (s, 3H). 13C-NMR (150 MHz, CDCl3) δ 157.7, 147.4, 146.6, 146.5, 144.2, 140.8, 140.0, 138.6, 137.9, 136.8, 136.6, 134.2, 134.0, 131.5, 131.2, 131.1, 130.8, 129.6, 129.5, 129.2 (2C), 128.9, 128.4, 124.5, 124.3, 124.2, 124.1, 123.9, 122.2, 121.9, 121.6, 121.1, 120.9, 120.8 (2C), 119.1, 116.6 (2C), 112.1, 112.0, 55.9 (2C).
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([Cl:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([Cl:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reaction time: 4.5 h
Yield: 92.2 %

Procedure:
To a mixed solution (1:1) of 2.5 ml of 4N hydrochloric acid and acetic acid was added 600 mg of ethyl 1-[6-(t-butylamino)-3-chloro-5-fluoropyridine-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 4.5 hours. After adding 2 ml of distilled water, the solution was allowed to cool and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 458 mg of the title compound as a pale yellow powder.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and ((S)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[N:24]1([C:30]2[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:35]=3)=[CH:17][C:9]1=2
Reactant: OB(O)c1ccnc(N2CCNCC2)c1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3ccnc(N4CCNCC4)c3)cc21

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (293 mg) was reacted with 2-(piperazin-1-yl)pyridine-4-boronic acid, pinacol ester as in General Procedure 4B to give the title compound as an off-white solid. m.p.=189° C., LCMS: m/z=489.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.98 (4H, m), 3.49 (6H, m), 3.71 (2H, m), 4.61 (2H, s), 5.29 (1H, s), 5.34 (1H, bs), 6.55 (2H, m), 6.64 (1H, dd, J=5.2, 1.4 Hz), 7.36 (1H, d, J=8.1 Hz), 7.52 (1H, s), 7.64 (1H, d, J=8.3 Hz), 7.77 (1H, d, J=2.0 Hz), 8.12 (1H, d, J=5.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:13]1[C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][S:16][C:12]1=[N:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CBr
Reactant: Cc1cc(N=C2NC3(CCCC3)CS2)ccc1[N+](=O)[O-]
Product: Cc1cc(N=C2SCC3(CCCC3)N2CC(C)C)ccc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:9]=[C:10]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cc1ccccc1-n1cc(Br)c2[nH]nc(N)c2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: Cc1ccccc1-n1cc(-c2cnn(C)c2)c2[nH]nc(N)c2c1=O
Temperature: 140 °C
Yield: 11.5 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step F of Example 1 (200 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (196 mg), tetrakis(triphenylphosphine)palladium(0) (72.4 mg), aqueous sodium carbonate solution (2 M, 0.630 mL) and N,N-dimethylformamide (3.0 mL) was heated with microwave irradiation at 140° C. for 3 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give the title compound (23.0 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH:15]3[CH3:17])[C:7]=12.[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][OH:22]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:22][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH:15]3[CH3:17])[C:7]=12
Reactant: OCc1ccc(F)cc1F
Reactant: Cc1c(C)n(CC2CC2C)c2c(Cl)nncc12
Product: Cc1c(C)n(CC2CC2C)c2c(OCc3ccc(F)cc3F)nncc12
Yield: 63.8 %

Procedure:
The title compound (trans) was prepared as a white powder in 63.8% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine and 2,4-difluorobenzyl alcohol.
Reaction SMILES: [C:1](NC1C=C(C#C)C=CC=1)(=[O:3])C.[N+:13]([C:16]1[CH:17]=[C:18]2[CH:24]=[C:23]([C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=3)[NH:22][C:19]2=[N:20][CH:21]=1)([O-])=O.[CH3:35][C:36](C)([O-:38])[CH3:37].[K+]>>[CH:36]([O:38][C:1](=[O:3])[NH:13][C:16]1[CH:17]=[C:18]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[NH:22][C:19]2=[N:20][CH:21]=1)([CH3:37])[CH3:35]
Reactant: CC(=O)Nc1cccc(-c2cc3cc([N+](=O)[O-])cnc3[nH]2)c1
Reactant: CC(C)(C)[O-]
Reactant: C#Cc1cccc(NC(C)=O)c1
Agent: [K+]
Product: CC(=O)Nc1cccc(-c2cc3cc(NC(=O)OC(C)C)cnc3[nH]2)c1

Procedure:
Was prepared analogously to example 9-2 starting from 3-(acetylamino)phenylacetylene. In the preparation of the intermediate N-[3-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-acetamide by cyclization reaction an higher equimolar amount of base (Potassium tert-butoxide) as in Example 2-2 is needed:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:9][CH:10]([CH3:14])[CH3:11])[N:12]=[CH:11]2
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Br)ccc21
Temperature: 105 °C

Procedure:
K2CO3 was added to a solution of 5-bromoindazole and in DMF. The mixture was heated to 105° C. After disappearance of 5-bromoindazole the reaction mixture was poured onto DCM/brine. The two layers were separated and the aqueous layer was extracted with DCM (2×) and checked by TLC. The combined organics were washed with H2O (2×) and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the resulting residue was purified by chromatography with 9.5:0.5 hexane/EtOAc to provide desired product (14p).