Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[H-].[Na+].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]>CN(C)C=O>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: COCCOCCBr
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCN1C(=O)[C@@]2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a solution of (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.27 g, 0.9 mmol) in dry N,N-dimethylformamide (15 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.054 g, 1.4 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 15 minutes and 1-bromo-2-(2-methoxyethoxy)ethane (0.33 g, 1.8 mmol) was added in one portion. The mixture was stirred at 60° C. for 6 h and concentrated in vacuo. Water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 40% ethyl acetate in hexanes to afford (8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.31 g, 85%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m, 1H), 7.15-7.08 (m, 1H), 7.05-6.96 (m, 2H), 6.46 (s, 1H), 6.21 (s, 1H), 4.73 (ABq, 2H), 4.20-4.04 (m, 4H), 4.05-3.83 (m, 2H), 3.80-3.69 (m, 2H), 3.64-3.56 (m, 2H), 3.51-3.44 (m, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 155.1, 144.5, 142.5, 138.2, 132.3, 128.6, 123.7, 123.2, 121.2, 111.5, 109.2, 99.3, 80.0, 71.9, 70.4, 68.1, 64.5, 63.9, 59.0, 57.9, 40.2; MS (ES+) m/z 397.9 (M+1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]1([C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][CH2:13][CH2:14][SH:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:5]1([C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:12][CH2:13][CH2:14][S:15][C:3]([NH:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN=C=O
Reactant: SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CNC(=O)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Methylisocyanate (243 mg) was dissolved in anhydrous dichloromethane (5 ml). To the solution were added N-triphenylmethylcysteamine (3.19 g: 0.33 equimolar amount) while cooling with ice. The reaction solution was stirred at room temperature for 4 hours and was concentrated under reduced pressure. The residue was dissolved in chloroform (50 ml), and the chloroform solution was well washed with water and a saturated solution of sodium chloride. Anhydrous sodium sulate was used to dry the chloroform layer which was then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a solvent system of hexane/ethyl acetate (5:1 v/v) to obtain the desired substance (297 mg) with a yield of 79%.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5]1.F[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[N:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH:15]=[CH:14]2.O>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:9][C@H:6]4[CH2:7][CH2:8][C@H:4]([NH2:3])[CH2:5]4)[CH:12]=3)[C:17]2=[O:21])=[CH:28][CH:27]=1
Reactant: N[C@H]1CC[C@H](O)C1
Reactant: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)C4)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
106 mg (4.20 mmol) of sodium hydride (95%) were suspended in 3 mL of dimethyl acetamide and 193 mg (1.40 mmol) of (1S,3S)-3-amino-cyclopentanol (34), dissolved in 1 mL of dimethyl acetamide, were added dropwise. After 1 h, 402 mg (1.42 mmol) of 2-(4-methoxy-benzyl)-6-fluoro-2H-isoquinolin-1-one (9), dissolved in another 3 mL of dimethyl acetamide, were added. The reaction mixture was stirred at 80° C. until the reaction was complete. The mixture was poured into water, extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 250 mg of the title compound (39). Rt=1.20 min (Method E). Detected mass: 365.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[NH2:40][C@@H:41]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:42]([N:44]([CH2:56][CH:57]([O:61][CH2:62][CH3:63])[O:58][CH2:59][CH3:60])[CH2:45][C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([NH:40][C@@H:41]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[CH:67][CH:66]=2)[C:42]([N:44]([CH2:56][CH:57]([O:61][CH2:62][CH3:63])[O:58][CH2:59][CH3:60])[CH2:45][C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:49]=[CH:48][CH:47]=2)=[O:43])=[O:17])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of 1-((3-benzylureido)methyl)cyclopropanecarboxylic acid (Compound VI-1) (182 mg, 0.77 mmol), hydroxybenzotriazol (126 mg, 0.51 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (98 mg, 0.51 mmol) in dichloromethane (1.5 ml) was added a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (125 mg, 0.25 mmol) and 4-dimethylaminopyridine (16 mg, 0.13 mmol) in dichloromethane (1.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetated (150 ml) and washed with saturated sodium bicarbonate (50 ml), water (10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Purif silica gel column chromatography (eluent: n-hexanae:ethylacetate=50:50 to 0:100) to obtain the title compound (175 mg, 97%).
Reaction SMILES: Cl.[SH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]#[N:14])=[CH:6][CH:5]=1>CO>[ClH:3].[NH2:14][C:13]1[S:2][C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: N#CCCC(=O)c1ccc(Cl)cc1
Reactant: S
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl and H2S gas are bubbled through a solution of the above nitrile (7.70 g, 40.0 mmol) in 100 ml of methanol at 10°-20° for 7 hours. The suspension is then stirred at RT overnight. It is dried, filtered, washed with ether and dried with suction under an N2 atmosphere to give 2-amino-5-(4-chlorophenyl)thiophene hydrochloric acid salt, a slightly purplish powder.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].Br[CH2:11][C:12]([CH2:14][C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16])=O.Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:11]=[C:12]([CH2:14][C:15]([NH:17][CH:18]2[C:28](=[O:29])[N:20]3[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]23)=[O:16])[N:4]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 51.1 %

Procedure:
Thiourea (663 mg), sodium bicarbonate (732 mg) and water (20 ml) were added to a stirred solution of 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid (2.11 g) in tetrahydrofuran (20 ml) under ice-cooling and stirred at the same temperature for an hour. After the resultant solution was adjusted to pH 4.0 with dilute hydrochloric acid, the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (1.01 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[NH2:7][C:5]1[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=[C:2]([N:1]=[CH:16][O:15][CH2:12][CH3:13])[N:6]=1
Reactant: CNC(=S)n1nc(N)nc1N
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=Nc1nc(N)n(C(=S)NC)n1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of the compound (500 mg) obtained in Example 31 and diethoxymethyl acetate (7 ml) was stirred at room temperature. After stirring for 1 hour, the resulting crystals were collected by filtration to give 480 mg of a white powdery solid (yield 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:19]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[N:19]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirring mixture of 4-chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide (48 mg, 0.096 mmol) and 1-methylpiperazine (16 μl, 0.0.144 mmol) in anhydrous tetrahydrofuran (5 ml) was added N,N-diisopropylethylamine (200 μl). The mixture was refluxed for 20 h. The mixture was cooled to room temperature and then rotary evaporated to dryness. The residue was purified by column chromatography and isolated as a tan solid (22 mg, 41%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.5, 4.5 Hz, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.37 (dd, J=1.5, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.74 (s, 1H), 3.57 (s, 2H), 2.47 (s, 8H), 2.29 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[N:3]1.O.NN>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]([NH2:21])=[N:3]1
Reactant: Cn1nc(N2C(=O)c3ccccc3C2=O)c(C#Cc2ccccc2)c1-c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nc(N)c(C#Cc2ccccc2)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of 2-[1-methyl-5-phenyl-4-(2-phenylethynyl)pyrazol-3-yl]isoindoline-1,3-dione (300 mg, 0.74 mmol), ethanol (5 mL) and hydrazine hydrate (56 μL, 1.11 mL) was stirred in a sealed tube at 90° C. for 1 h and cooled to room temperature. The reaction mixture was filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, isohexane/ethyl acetate 7:3 to 1:1) yielding the title compound as a solid (150 mg).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[C:8]1([C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][C:15]=2[C:28](OCC)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH3:2][C:1]1[N:3]=[C:28]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([C:14]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[O:5][N:4]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)n1
Yield: 85 %

Procedure:
A mixture of acetamidoxime (148 mg, 2.0 mmol) and powdered 4A molecular sieves (0.5 g) in THF (5 mL) is treated with 60% NaH in oil (80 mg, 2.0 mmol) for 15 min at ambient temperature. The reaction is treated with ethyl 4-phenyl-8-(trifluoromethyl)quinoline-3-carboxylate (173 mg, 0.50 mmol) and heated at reflux for 22 h. The reaction is cooled, concentrated, treated with water, and extracted with dichloromethane. The extracts are dried with MgSO4, concentrated, and the residue chromatographed with 20:80 ethyl acetate:hexane to afford the title compound as an off-white solid (151 mg). MS (ES) m/z 356.1; HRMS: calcd for C19H12F3N3O, 355.0932; found (ESI, [M+H]+), 356.1008.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1>>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[N:8]=3)=[O:14])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccn(-c2ccncc2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2ccncc2)n1
Yield: 73.7 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (47.5 mg, 0.251 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (70 mg, 0.251 mmol). The precipitate that formed during the reaction was filtered out of the reaction mixture was washed with 2×5 ml of water and dried with vacuum at 40° C. Yield 73.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 4.31-4.42 (m, 2H), 4.43-4.54 (m, 1H), 6.90 (d, 1H), 7.01 (dd, 1H), 7.79-8.01 (m, 5H), 8.39 (d, 1H), 8.66-8.73 (m, 2H), 8.77 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:29])[N:7]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:6]=12.C([Sn](=O)CCCC)CCC.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:48][N:47]=[N:46][N:28]=4)=[CH:19][CH:20]=3)[C:8](=[O:29])[N:7]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:6]=12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 41.6 %

Procedure:
A mixture of 4′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.33 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (3.5 g) and toluene (30 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 41%).
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:32])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33]
Reactant: CN1CCNCC1
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc3c(c2)C2(CCN(C(=O)/C=C/c4ccccc4C(F)(F)F)CC2)C(=O)N3C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.04 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added 1-methyl-piperazine (6.0 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI (18 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) and the mixture was stirred overnight at rt under N2. The reaction mixture was washed with 1 N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by prep TLC to give (E)-1-methyl-5-(4-methylpiperazine-1-carbonyl)-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one (12 mg, 57%). 1H NMR (CD3OD): 1.90 (m, 4H), 2.95 (s, 3H), 3.30 (m, 11H), 3.95 (m, 1H), 4.20 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.50 (m, 3H), 7.66 (m, 1H), 7.77 (m, 1H), 8.00 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N(Cc2ccc(F)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 Milliliters of acetonitrile was added to 500 mg of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole, 0.42 ml of 4-fluorobenzyl bromide and 746 mg of potassium carbonate and the mixture was stirred for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the resulting residue, which was then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The residue was subjected to silica gel column chromatography to give crude crystals from the chloroform/methanol (100/2) eluate. The crude crystals were recrystallized from ethyl acetate to give 314 mg of 4-[N-(4-cyanophenyl)-N-(4-fluorobenzyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[C:37]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:13]1([C@H:11]([O:10][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:46][S:43]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:45])=[O:44])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)c5ccccc5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 1 using 1-{4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and benzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.Cl.CNC>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[N:18]([CH3:19])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (65) (229 mg, 1 mmol, AalenChem) in DCM (5 mL) was added TEA (202 mg, 2 mmol) and HATU (414 mg, 1.2 mmol). The reaction mixture was stirred for 5 min and dimethylamine hydrochloride (81 mg, 1 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (66) (220 mg, 0.85 mmol, 85% yield) as a light yellow oil.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[S:19])=[CH:13][CH:12]=1
Reactant: CCCCC(=N)N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred mixture, prepared by reacting 4.6 g. sodium with 300 ml. dry acetone at room temperature was cooled to 5°C. and 27.3 g. valeramidine hydrochloride was added in one portion. After 20 minutes there was added dropwise during thirty minutes, a solution of 33.8 g. 4-chlorophenyl isothiocyanate in 200 ml. dry acetone while the temperature was maintained at 5° to 10°C. The mixture was stirred for 18 hours at room temperature, filtered and the filtrate was evaporated to dryness under reduced pressure. A solution of the residue in 300 ml. ether was chilled and treated with ethereal hydrogen chloride until acidic and the resulting solid was filtered to give, after recrystallization from acetonitrile 51.1 g. 1-(4-chlorophenyl)-3-(pentanimidoyl)-2-thiourea hydrochloride; m.p. 164°-166°C.