Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:19])[C@@H:7]([NH:11]C(=O)OC(C)(C)C)[CH2:8][CH2:9][CH3:10])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C:6]([N:4]1[CH2:3][CH:2]([OH:1])[CH2:5]1)=[O:19]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](N)C(=O)N1CC(O)C1
Reaction time: 2 h
Yield: 176 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-hydroxyazetidin-1-yl)-1-oxopentan-2-ylcarbamate (Compound A2) (3.5 g, 12.8 mmol) in anhydrous DCM (50 mL) was added TFA (18 mL, 242 mmol) dropwise at 0° C. under N2(g). The reaction mixture was stirred at r.t for 2 h and then concentrated under reduced pressure. The residue was dissolved in DCM and concentrated under reduced pressure to remove the residue of TFA. This procedure was repeated twice with DCM and twice with MeOH. To the residue was added diethyl ether and decanted (×2). The crude product was dried in vacuo give the title compound (3.88 g) used in the next step without further purification. LCMS (M+H)+: 173.1
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:3]1.CCOC(/[N:21]=N/C(OCC)=O)=O.N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C1COCC1.O>[NH2:21][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:3]1
Reactant: CCO[PH](=O)CCCCC1=CC(O)CC1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: [N-]=[N+]=N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCO[PH](=O)CCCCC1=CC(N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of (±)-ethyl (3-hydroxycyclopentenyl)butylphosphinate (7) (2.98 g, 12.8 mmol), DEAD (4.2 cm3) and HN3 (13.5 cm3 of a 1.9 M solution in benzene) in anhydrous THF (150 cm3) at 0° C. was added triphenylphosphine (13.43 g, 51.4 mmol) in small portions over a period of 1 hour. The reaction mixture was allowed to warm to room temperature and stirring continued for 12 hours. The reaction mixture was then heated to 50° C. for 3 hours after which time then water (2 cm3) was added and heating continued for a further 2 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between aqueous HCl (1 M, 40 cm3) and DCM (40 cm3). The organic layer was separated and further extracted with water (3×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude product was purified by ion exchange chromatography (Dowex 50, H+), eluting first with water until the eluate was colourless and the pH 7. On further elution with aqueous ammonium hydroxide (1 M), ninhydrin positive fractions were collected and combined and the solvent was removed in vacuo. Recrystallisation from ethanol/acetone followed by drying gave the desired title compound (12) as a pale yellow oil (2.82 g, 95%): 1H-NMR (300 MHz, CDCl3) δH 0.88 (3H, 2×d, J=6.9 and 7.5 Hz, PCH2CH2CH2CH3),0.91 (3H, 2×d, J=7.2 and 7.2 Hz, PCH2CH2CH2CH3), 1.21-1.98 (9H, m, POCH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3,PCH2CH2CH2CH3), 2.38-2.71 (4H, m, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′), 3.87-4.31 (5H, m, POCH2CH3, C(3)—NH2, C(3)—H), 6.51 (1H, d, J=9.6 Hz, C(2)—H); 13C-NMR (75 MHz, CDCl3) δC 13.43 (s, PCH2CH2CH2CH3),16.39 and 16.47 (d, 3JPOCC=6.00 Hz, POCH2CH3), 23.41 and 23.46 (2×d, 2JPC=3.38 and 3.75 Hz, PCH2CH2CH2CH3), 23.63 and 23.84 (d, 3JPC=15.90 Hz, PCH2CH2CH2CH3),27.15 and 28.47 (2×d, JPC=99.0 and 99.0 Hz, PCH2CH2CH2CH3), 31.93 and 32.09 (2×d, 3JPC=11.63 and 11.70 Hz, C(4)), 34.93 and 35.04 (2×d, 2JPC=8.25 and 8.55 Hz, C(5)), 58.86 and 59.09 (2×d, 3JPC=17.03 and 17.33 Hz, C(3)), 60.11 and 60.19 (d, 2JPOC=6.23 Hz, POCH2CH3), 135.63 and 137.72 (d, JPC=156.75 Hz, C(1)), 150.47 and 150.66 (2×d, 2JPC=13.88 and 13.95 Hz, C(2)); 31P-NMR (121 MHz, CDCl3) δP 43.18 and 43.28; MS (CI, CH4) m/z 232.0 (16%) (MH+), 215.1 (100), 446.0 (18), 260.2 (14). Synthesis of (±)-ethyl [3-(t-butyloxycarbonyl)aminocyclopentenyl]butylphosphinate (13)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2S[CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)[CH2:18][CH2:17]1)=[O:13].ClCC1[O:35]C=C(C(OC)=O)N=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:35][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)[CH2:18][CH2:17]1)=[O:13]
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Reactant: COC(=O)c1coc(CCl)n1
Product: COC(=O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1

Procedure:
Methyl 2-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}-1,3-oxazole-4-carboxylate 9 was prepared, according to the procedure described for compound 7, using methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate. Yield: 410 mg, 45%.
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][C:6]([CH2:8][NH2:9])=O.Cl.[CH2:11]([O:14][NH2:15])[CH:12]=[CH2:13].[CH3:16]O>>[ClH:2].[CH2:11]([O:14][N:15]=[C:6]1[CH2:8][NH:9][CH:16]=[N:4][CH2:5]1)[CH:12]=[CH2:13]
Reactant: C=CCON
Reactant: NCC(=O)CN
Reactant: CO
Agent: Cl
Solvent: O
Product: C=CCON=C1CN=CNC1
Yield: 57 %

Procedure:
1,3-Diaminoacetone dihydrochloride monohydrate (2.00 g, 11.2 mmol) was dissolved in refluxing methanol and O-2-propenylhydroxylamine hydrochloride (2.40 g, 21.9 mmol) was added. After refluxing for 96 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 48 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 1.20 g (57%) of white material. Mp. 164.5° C.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH3:18])=[CH:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([O:9][CH2:10][O:11][CH3:12])[C:7]=1[CH3:8].C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+].C1C[O:34][CH2:33]C1>>[CH2:17]([O:16][C:3]1[C:4]([O:27][CH3:26])=[C:5]([O:13][CH2:14][CH3:15])[C:6]([O:9][CH2:10][O:11][CH3:12])=[C:7]([CH3:8])[C:2]=1[CH:33]=[O:34])[CH3:18]
Reactant: CN(C)C=O
Reactant: CCOc1cc(OCC)c(OCOC)c(C)c1Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCOc1c(C=O)c(C)c(OCOC)c(OCC)c1OC
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
43.6 g of 5-bromo-2,4-diethoxy-6-methyl-1-methoxymethyloxybenzene prepared in Referential Example 8 was dissolved in 220 ml of THF, and 100 ml of n-butyllithium (1.6M n-hexane solution) was dropwise added thereto at -70° C. The mixture was stirred at -40° C. for 30 min, and 11.9 g of dimethylformamide was dropwise added thereto. The temperature of the reaction mixture was returned to room temperature, and an aqueous ammonium chloride solution was added thereto, followed by extracting with ethyl acetate. The organic phase was washed with-water, dried, concentrated and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=90:10) to prepare 19.2 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH:25]([CH3:28])[CH:26]=[O:27].O>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH:25]([CH3:28])[CH:26]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[OH:27]
Reactant: Clc1cc(I)ccn1
Reactant: COc1ccc(Cl)c(C(C)C=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(C(C)C(O)c2ccnc(Cl)c2)c1
Reaction time: 1.5 h
Yield: 66 %

Procedure:
2-Chloro-4-iodopyridine (1.03 g, [CAS Reg. No. 153034-86-7]) was dissolved in THF (50 mL) and a solution of isopropylmagnesiumchloride-lithium chloride complex (14% in THF, 3.13 mL) was added over a period of 3 minutes at r.t. The mixture was cooled in an ice bath and 2-(2-chloro-5-methoxy-phenyl)-propionaldehyde (710 mg) dissolved in THF (20 mL) was added dropwise over a period of 10 minutes. Stirring was continued for 1.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the desired compound as a yellow oil (734 mg, 66%). MS (m/e)=312.0 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.Br[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24])[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:36][CH2:35]3)=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)cc23)cc1Cl
Temperature: 60 °C
Yield: 10.9 %

Procedure:
N-(2-chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy) phenyl)-N′-methylurea (125 mg) was added to dimethylformamide (1.5 ml), and then tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate (141 mg) and potassium carbonate (93 mg) were added thereto and the mixture was heated at 60° C. for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain tert-butyl 4-(((4-(3-chloro-4-((methylamino)carbonyl) aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (21 mg) as light yellow crystals. These were dissolved in trifluoroacetic acid (1.0 ml), and the solution was stirred for 10 minutes at room temperature. Water (2 ml) was added, the mixture was neutralized with sodium bicarbonate, and the precipitated crystals were filtered out to obtain the title compound (16 mg).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.C(Cl)(Cl)Cl.[O:31]=[C:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:33]([OH:35])=[O:34]>CO>[CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[O:31]=[C:32]([CH2:36][CH2:37][C:38]([O-:40])=[O:39])[C:33]([O-:35])=[O:34]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C([O-])CCC(=O)C(=O)[O-]

Procedure:
1.617 g. of vincamine (0.005 mole) is dissolved in 15 ml. of chloroform, and 0.8 g. (0.055 mole) of 2-ketoglutaric acid previously dissolved in 5 ml. of methanol is added. After concentration of the resulting solution in a rotary evaporator until a volume of 5 ml. is obtained, 1.75 g. of vincamine 2-ketoglutarate is obtained. By subsequent successive concentrations, an additional amount of 0.5 g. of salt is obtained. A total of 2.25 g. is thus obtained (yield 90%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]([C:12]1[N:13]=[N:14][C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:16][C:17]=1[CH3:18])[NH2:11].C(N(CC)CC)C>O1CCOCC1>[CH3:18][C:17]1[C:12]2[N:13]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][N:10]=2)[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=1
Reactant: Cc1cc(N2CCOCC2)nnc1NN
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)nn2c(-c3ccccc3)nnc12

Procedure:
The compounds wherein R is phenyl are prepared by reaction of the corresponding 3-hydrazino-4-alkyl-6-morpholinopyridazine with benzoyl chloride. For example, 3.5 grams of benzoyl chloride are added to a solution of 1.48 grams of 3-hydrazino-4-methyl-6-morpholinopyridazine and 1.8 grams of triethylamine, in 200 milliliters of dioxane and the mixture is refluxed for 3 hours. After evaporation of the solvent and washing with water, the 8-methyl-6-morpholino-3-phenyl-s-triazolo[4,3-b]pyridazine product is obtained, recrystallized from ethanol and found to melt at 271°-273° C. Compounds wherein R is phenyl can also be prepared by reacting a 3-chloro-4-loweralkyl-6-morpholinopyridazine with benzoyl hydrazide, preferably in equimolar proportions and at a temperature from the fusion point of the mixture to about 200° C. The latter reaction can be carried out without a solvent or in a solvent medium such as diethylene glycol methyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4]([N+:21]([O-])=O)[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4]([NH2:21])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A solution of 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.3 g, 7.39 mmol) in MeOH (37 mL) and THF (37 mL) was treated with NH4Cl (11.86 g, 222 mmol) followed by the portion-wise addition of zinc dust (4.83 g, 73.9 mmol) and the mixture stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.4 g, 67%). MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([CH:33](O)[CH3:34])[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16].CS(Cl)(=O)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([CH:33]=[CH2:34])[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Reaction time: 8 h

Procedure:
Triethylamine (3.0 ml, 21.8 mmol) was added to a solution of N-{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide of Example 56 (1.74 g, 4.36 mmol) in DCM (40 ml) at 0° C. Then methanesulfonyl chloride (0.675 ml, 8.73 mmol) was added slowly at 0° C. After addition stirring was continued at RT overnight. The reaction mixture was then diluted with DCM and washed with 1 M HCl. The organic layer was dried (Na2SO4), filtered and concentrated. Crystallization in DCM afforded the title compound. 1H NMR (400 MHz, CDCl3+a drop of MeOH-d4): 1.25 (31-1, d), 4.31 (1H, distorted dd), 4.39 (1H, distorted dd), 4.55 (1H, m), 5.38 (1H, d), 5.76 (1H, d), 6.60 (1H, dd), 6.63 (1H, d), 6.79 (1H, s), 7.55 (1H, d), 7.70 (1H, distorted d), 7.73 (1H, d), 7.82 (1H, distorted dd), 7.96 (1H, d).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:36])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:37]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O.O>CN(C=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:36])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:28])[C:23]([O:25][CH3:37])=[O:24]
Reactant: Cc1cnc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)cn1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@]1(OC(=O)c2cnc(C)cn2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (2.50 g) is dissolved in DMF (11 mL) and cooled to 0° C. DBU (1.68 g) is added, followed by dimethyl sulphate (953 mg) after 10 minutes. The reaction is stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, then dried over sodium sulfate. Evaporation affords 5-methylpyrazine-2 carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Observed mass (M+H) 511.
Reaction SMILES: [N:1]#[C:2]N.[C:4](Cl)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][C:14]1[C:15]([NH2:21])=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[CH3:13][C:14]1[C:15]2[NH:21][C:2]([NH:1][C:4](=[O:11])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:20][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CN
Reactant: Cc1cccc(N)c1N
Solvent: c1ccncc1
Product: Cc1cccc2nc(NC(=O)c3ccccc3)[nH]c12
Temperature: 25 °C

Procedure:
Cyanamide (3.44 g.) is dissolved in 69 ml. of pyridine and the mixture is held at 0°-4° C. While stirring, benzoyl chloride (11.5 g.) is added in portions. The reaction mixture is maintained at 0°-4° C. for 15 minutes. 3-Methyl-o-phenylenediamine (10 g.) is then added to the reaction mixture, and the resulting product is kept at room temperature for a few hours and then heated on a steam-bath for about 2.5 hours. After cooling to room temperature, the mixture is evaporated under reduced pressure, poured into 200 ml. water, and rubbed until solid. The product is removed by suction-filtration, dissolved in 5% aqueous sodium hydroxide solution, and clarified by gravity filtration. The benzimidazole derivative is precipitated by the addition of the alkaline solution to a slight excess of dilute acetic acid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[C:14]1[CH:24]([CH3:26])[CH3:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:30]=[O:31])C>CCOC(C)=O>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15]([CH:30]=[O:31])=[C:14]1[CH:24]([CH3:26])[CH3:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2cc(C(C)C)n(Cc3ccccc3)c2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Reaction time: 0.5 h

Procedure:
POCl3 (0.48 ml, 5.23 mmol) was added dropwise to anhydrous DMF (2 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole (Compound 4, 583 mg, 2.09 mmol) in anhydrous DMF (8 ml) at 0° C. under argon. The reaction was stirred for 1 h at 0° C. and 30 min at room temperature, diluted with EtOAc, washed with aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a light yellow syrup.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 2-acetamido-5-bromobenzotrifluoride (665 mg, 2.436 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.4 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 700 mg (90%) of crude 2-acetamido-5-bromo-3-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to offer 610 mg (78.8%) of pure compound as white needles. Mp: 193°-5° C., 1H NMR (CDCl3): δ2.250 (s, 3H), 7.346 (s, 1H), 8.039 (s, 1H); 8.247 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=2)=[C:4]([O:22]C)[CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=2)=[C:4]([OH:22])[CH:3]=1
Reactant: COc1ccc(C(=O)Nc2cc(OC)c(Cl)cc2OC)cc1F
Solvent: ClCCl
Product: O=C(Nc1cc(O)c(Cl)cc1O)c1ccc(O)c(F)c1
Reaction time: 20 h
Yield: 91.3 %

Procedure:
Boron trifluoride dimethyl sulfide complex (70 mL) was added into a mixture of N-(4-chloro-2,5-dimethoxyphenyl)-3-fluoro-4-methoxybenzamide (1.75 g, 5.15 mmol) and CH2Cl2 (35 mL). After stirring for 20 h, the solvent and the excess reagent were evaporated under a nitrogen stream in the hood. The residue was taken in a mixture of ice and HCl (1N) and extracted with EtOAc. The organic layer was washed with HCl (1N) and dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/EtOAc 5/3/2, and AcOH 10 mL per 1 liter of the eluting solvent) gave a white solid (1.4 g, 91% yield, m.p. 254-256° C.); MS m/e 296 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:9][C@@H:10]([CH3:15])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[N:23]=[C:24]=[O:25].N[C:27]1[CH:28]=CC2N(C)C(=O)[C@H](C)N=C(C3C=CC=CC=3Cl)C=2[C:47]=1Br.[NH2:49][CH2:50][CH:51]([OH:54])[CH2:52][OH:53]>CC(C)=O.O>[Br:1][C:2]1[C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:9][C@@H:10]([CH3:15])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:49][CH2:50][CH:51]1[CH2:52][O:53][C:27]([CH3:28])([CH3:47])[O:54]1)=[O:25]
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N=C=O)c2Br)N(C)C1=O
Reactant: NCC(O)CO
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(NC(=O)NCC3COC(C)(C)O3)c2Br)N(C)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (S)-[6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate [obtained in accordance with details in Example 1(f) from 4 g (0.01 mol) of (S)-7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one] in acetone is treated with a solution of 3.8 g (0.04 mol) of 3-amino-1,2-propanediol in 10 ml of water and 50 ml of acetone, the mixture is stirred at room temperature for 12 hours and extracted with methylene chloride. The organic extract is dried over sodium sulphate and evaporated, whereupon the residue is chromatographed on silica gel while eluting with chloroform. There is obtained 1-[(S)-6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]urea of melting point 135° (decomposition); [α]25D =+7.6° (0.8 percent solution in methanol).