Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.ClC1C=C(C=CC=1F)N>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1)[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: Cn1cc(N)cc(Cl)c1=O
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1C

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A4) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound as a dark blue-green foam. tR: 5.19 min (HPLC 1); ESI-MS: tR=1.27 min, [M+H]+ 476/478/480 (LC-MS 1); TLC: Rf=0.53 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1[CH:25]=[CH:26][C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.[C:36]([C:38]1[CH:47]=[CH:46][C:41]([C:42]([NH:44][NH2:45])=O)=[CH:40][CH:39]=1)#[N:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl.C(N(CC)CC)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1[CH:25]=[CH:26][C:27]1[O:28][C:42]([C:41]2[CH:46]=[CH:47][C:38]([C:36]#[N:37])=[CH:39][CH:40]=2)=[N:44][N:45]=1
Reactant: O=C(O)C=Cc1nnc(-c2ccc(OCC(F)(F)F)cn2)n1-c1ccccc1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: BrC(Br)(Br)Br
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(-c2nnc(C=Cc3nnc(-c4ccc(OCC(F)(F)F)cn4)n3-c3ccccc3Cl)o2)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a 100 mL flask with 3-{4-(2-Chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-acrylic acid 8 (0.18 g, 0.368 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.20 g, 1.55 mmol) and a drop of DMF. The reaction was kept at ambient temperature for 3 h. The solvent was removed and the residue was further dried under high vacuum and cooled to −20° C. Dichloromethane (10 mL) was added, followed by 4-Cyano-benzoic acid hydrazide (0.18 g, 1.1 mmol) and triethylamine (0.5 mL). The reaction mixture was kept at this temperature for 0.5 h and then ambient temperature for 1 h. The solvent was removed and the crude 4-Cyano-benzoic acid N′-(3-{4-(2-chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-acryloyl)-hydrazide was used for the next step. 4-Cyano-benzoic acid N′-(3-{4-(2-chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-acryloyl)-hydrazide was dissolved in dichloromethane (10 mL) and triphenylphosphine (0.19 g, 0.736 mmol), carbon tetrabromide (0.24 g, 0.736 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 4-[5-(2-{4-(2-Chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-vinyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile as a yellow solid. Yield: 0.07 g, 30%.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>>[NH:20]1[C:19]([NH:18][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=2)=[O:13])=[N:23][N:22]=[N:21]1
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1cccc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: CCCCc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 34.5 %

Procedure:
2.4 g of 6-n-butyl-2-pyridinecarboxylic acid, 15 ml of thionyl chloride and 0.97 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.97 g of N-(5-tetrazolyl)-6-n-butyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](O)(=[O:34])[CH2:32][CH3:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)O
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 68.1 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), propionic acid (40 μL, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (116 mg, 68%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1.CCN=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C.Cl.Cl.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH:40]1([NH:41][C:30]([CH:28]2[CH2:27][N:26]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH2:12][C:11]([C:17]5[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=5)([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=4)=[CH:7][C:2]=3[Cl:1])[CH2:29]2)=[O:31])[CH2:38][CH2:39]1
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a stirred solution of 1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.190 mmol) in dry DMF (3 mL) was added EDCl.HCl (0.055 g, 0.280 mmol), DIPEA (0.049 g, 0.380 mmol) and cyclopropyl amine (0.011 g, 0.190 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (10 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (3×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford off white solid (0.020 g, 20%). 1H-NMR (400 MHz, CDCl3) δ: 0.50-0.53 (m, 2H), 0.77-0.82 (m, 2H), 2.72-2.76 (m, 1H), 3.26-3.30 (m, 1H), 3.60 (d, 1H, J=17.12 Hz), 4.00 (d, 1H, J=17 Hz), 4.23-4.33 (m, 4H), 5.72 (bs, 1H), 6.47 (d, 1H, J=8.6 Hz), 7.40 (dd, 1H, J1=8.44 Hz, J2=1.88 Hz), 7.46 (d, 1H, J=1.8 Hz), 7.62 (s, 2H); LC-MS (m/z): [M−H] 563.50.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH3:23][NH:24][CH3:25].O>CO.S(=O)(=O)(O)O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[N:24]([CH3:25])[CH3:23])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (6 g; 18.6474 mmole) in 33% w/w dimethylamine in methanol (50 ml) was heated at 100° C. under pressure (autoclaved) for 24 hours. The mixture was cooled, and treated with water, concentrated, and extracted with chloroform. The extract was washed with water, dried and evaporated to give a brown solid. The solid was heated in 70% sulphuric acid (150 ml) on a steambath for 6 hours. The mixture was cooled and the pH adjusted to about 7 before extraction into chloroform. The extract was dried and evaporated to give a yellow solid (1.25 g). NMR and mass spectra were consistent with the required structure.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:31])([F:30])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.[F:32][C:33]([F:40])([C:36]([F:39])([F:38])[F:37])[CH2:34][OH:35].C(N(CC)CC)C>C(OCC)(=O)C>[F:6][C:7]([F:30])([F:31])[C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([O:35][CH2:34][C:33]([F:40])([F:32])[C:36]([F:39])([F:38])[F:37])=[O:28])[CH:21]=1
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C=Nc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2C(F)(F)F)c1)OCC(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
First, to an anhydrous tetrahydrofuran solution (15 ml) of 0.5 g of N-(2,4-bistrifluoromethylphenyl)3-isocyanatobenzamide produced in Example 10-1 were added 0.40 g of 2,2,3,3,3-pentafluoro-n-propanol and 0.13 g of triethylamine, and the resultant mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate (20 ml), and an organic layer was washed with a 1N sodium hydroxide aqueous solution and 1N hydrochloric acid. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.49 g (yield 70%) of the title compound.
Reaction SMILES: Cl.[CH3:2][CH2:3][CH:4]([NH:7][NH2:8])[CH2:5][CH3:6].[C:9](#[N:13])[CH2:10][C:11]#[N:12].[CH2:14](N(CC)CC)[CH3:15]>CO>[NH2:12][C:11]1[N:7]([CH:4]([CH2:5][CH3:6])[CH2:3][CH3:2])[N:8]=[C:14]([CH3:15])[C:10]=1[C:9]#[N:13]
Reactant: N#CCC#N
Reactant: CCN(CC)CC
Reactant: CCC(CC)NN
Agent: Cl
Solvent: CO
Product: CCC(CC)n1nc(C)c(C#N)c1N
Yield: 101.8 %

Procedure:
11.9 g of 3-pentylhydrazine hydrochloride (Part A), 11.7 g of 1-ethoxyethylidine malononitrile and 26.0 g of triethylamine were dissolved in 100 mL of methanol and refluxed for a period of 20 h. The solvent was stripped in vacuo and partitioned the residue with 100 mL each of water and ethyl acetate and extracted the aqueous layer with 2*50 mL of ethyl acetate. The combined organic extracts were washed with brine, dried and stripped in vacuo to afford 16.8 g of brown oil. The oil was purified by flash column chromatography (1:100 MeOH/dichloromethane eluent) to afford 11.7 g (71%) of desired pyrazole derivative as a white crystalline solid (mp. 117-118° C.). Anal. calcd. for C10H16N4: C, 62.47; H, 8.40; N, 29.14. Found: C, 62.17; H, 8.39; N, 29.18.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.[F:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[F:22][C:23]1[C:28]([C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]4[CH:13]=[C:12]([C:37]5[CH:36]=[CH:35][N:34]=[C:33]([F:32])[CH:38]=5)[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1cccnc1F
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method BB12 above, but using (S)-7-bromo-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[N-:8]=[N+:9]=[N-:10].[Na+]>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH2:6][N:8]=[N+:9]=[N-:10])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCN=[N+]=[N-]
Temperature: 70 °C

Procedure:
A mixture of 2-bromoethyl acetate (500 μl, 4.54 mmol) in N,N-dimethylformamide (DMF) (2.0 mL) was treated with sodium azide (295 mg, 4.54 mmol) and then heated to 70° C. for 2 hours. The mixture was diluted with water and then extracted with ether. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) d=4.29-4.19 (m, 2 H), 3.53-3.44 (m, 2 H), 2.11 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([NH:15][C@H:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14].O[Li:34].O>>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([NH:15][C@H:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:26][CH:27]=1)[CH3:17])=[O:14].[Li+:34]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CCCCN2Cc2cccc(C(F)(F)F)c2)cc1
Reactant: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1CCCCN1Cc1cccc(C(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E4) (20 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((1S)-1-(1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D21) (45 mg). (LiOH H2O: 1.75 eq; reaction time: 3 hrs)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Reactant: COCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol, diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (67 mg, 75%) as a colorless gum: [α]25589=−9.4° (c=0.16, methanol); ES-HRMS m/e calcd for C22H28N4O4S (M+H)+ 445.1904, observed 445.1904; 1H NMR (300 MHz, DMSO-d6) δ 1.12 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.12 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.36 (s, 3H, SO2CH3), 3.61 (t, J=5.3 Hz, 2 H, OCH2), 3.89 (m, 1H, ArCHCO), 4.12 (t, J=5.3 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.95 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.11 (d, Jm=1.6 Hz, 1H, Ar), 8.11 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(F)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 13A; 1.5 mmol, 1 equivalent) were dissolved in 64 ml of THF and 12 ml of methanol, 7.5 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT overnight. 8 ml of 1 N aqueous hydrochloric acid were then added, and the mixture was concentrated under reduced pressure. The solid formed was filtered off and washed with water. This gave 429 mg of the title compound (80% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.[N+](=[CH2:30])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([O:19][CH3:30])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: COC(=O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxy-2-hydroxyethylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-2-hydroxyethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][CH3:13])OC1C=CC=CC=1)#[N:2].[NH:14]1[CH2:16][CH2:15]1>C(#N)C>[C:1]([NH:3][C:4]([N:14]1[CH2:16][CH2:15]1)=[N:12][CH3:13])#[N:2]
Reactant: CN=C(NC#N)Oc1ccccc1
Reactant: C1CN1
Solvent: CC#N
Product: CN=C(NC#N)N1CC1
Yield: 77 %

Procedure:
N-Cyano-N'-methyl-O-phenylisourea (0.471 g, 2.69 mmol) was added during 2 minutes to aziridine (0.521 g, 12.1 mmol) at 20° with stirring. Immediate solution occurred, some heat was evolved, and after 5 min a solid precipitate was formed. After 90 min excess aziridine was removed in an air stream at 20°, leaving an oily solid residue. This was dissolved in acetonitrile (10 ml) and the solution was absorbed on to silica gel (1.0 g), and remaining volatiles were removed by evaporation under reduced pressure at 20°. The solid obtained was added to the top of a column of silica gel (19.7 g, length 15 cm, diameter 2 cm) and the column eluted with acetonitrile. The elution of phenol was followed by TLC and after it was complete, subsequent eluate was collected and gave on evaporation to dryness under reduced pressure N-cyano-N'-methyl-1-aziridinoamidine (0.257 g, 77%), m.p. 130°-132.5°, Rf 0.64-0.66 (silica, acetonitrile).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[S:27][N:26]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>O1CCCC1.C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[S:27][N:26]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nsc(=O)[nH]3)ccc2c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3nsc(=O)[nH]3)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
Tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.050 g, 0.10 mmol) was dissolved in tetrahydrofuran (3 ml) and a solution (2 ml) of 4N hydrogen chloride in ethyl acetate was added. The mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and diisopropyl ether-ethyl acetate (2:1) was added to the residue to give 3-(aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinone hydrochloride (0.041 g, 94%) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([N:19]=[C:20]=[S:21])=[O:18])=[CH:15][CH:14]=1>CCOCC>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:20]([NH:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([CH3:12])=[CH:14][CH:15]=1)=[S:21]
Reactant: CNC(=O)c1ccccc1N
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccc(C)cc1
Yield: 98 %

Procedure:
To a stirred mixture of 8.0 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 10 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 1 hour. After stirring several hours, the solid was collected, giving 17.1 g of the desired product as white crystals, mp 198°-200° C. (dec.).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[H][H].[CH2:16]([C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[CH:5][C:6]#[N:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 10.5 g (0.437 mole) of mineral oil free sodium hydride in 1.2 liters of tetrahydrofuran was added dropwise 58.4 g (0.328 mole) of diethylcyanomethyl phosphonate. After the hydrogen evolution had ceased ca 60 min, 69.4 g (0.3 mole) of 2-benzyl-4-chlorobenzaldehyde, in 75 ml of tetrahydrofuran was added dropwise. The mixture was stirred overnight at room temperature. The tetrahydrofuran solution was decanted, and concentrated at room temperature. The residue was partitioned between 2 liters of water and 1.5 liters of ether. The ether solution was separated, washed with water, and dried with sodium sulfate. The ether was removed at reduced pressure to give a yellow oil which was used without further purification.