Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)[N:13]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.19 ml of 4-trifluoromethyl-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 146 mg of expected product is obtained.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:16](=[O:27])[C:15]3[CH:28]=[C:29](I)[CH:30]=[CH:31][C:14]=3[NH:13][C:12]2=[O:33])=[CH:7][CH:6]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:16](=[O:27])[C:15]3[CH:28]=[C:29]([C:1]#[C:2][CH3:3])[CH:30]=[CH:31][C:14]=3[NH:13][C:12]2=[O:33])=[CH:7][CH:6]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2NC(=O)[C@@H]1c1ccc(Cl)cc1
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Propyne (2 mL) was condensed in a sealed tube at −78° C. Then, (3S)-3-(4-Chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-1,4-benzodiazepine-2,5-dione (200 mg, 0.362 mmol), copper iodide (15 mg, 0.0788 mmol), dichlorobis(triphenylphosphine)palladium (II) (39 mg, 0.0556 mmol), triethylamine (2 mL), and acetonitrile (4 mL) were added. The sealed tube was closed and the reaction mixture was allowed warm up to room temperature. After 12 h, the reaction mixture was cooled to −78° C. and the sealed tube was opened and allowed to warm up to room temperature under vigorous stirring. Then, solvents were evaporated in vacuo and the residue was purified by column chromatgraphy on silica (EtOAc/Hexanes, 1:1) to give the title compound as colorless solid (150 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 1.73 (d, J=7.1 Hz, 3H), 2.06 (s, 3H), 5.24 (s, 1H), 6.49 (q, J=7.1 Hz, 1H), 6.62–6.65 (m, 3H), 6.93 (d, J=8.4 Hz, 2H), 7.20 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.79 (d, J=2.0 Hz, 1H), 8.57 (br s, 1H). Mass spectrum (LCMS, ESI pos.): Calcd for C26H20Cl2N2O2: 463; found: 464 (M+H)+.
Reaction SMILES: C(O[CH2:6][C:7]([CH3:28])([CH3:27])[CH:8](N=C=O)[O:9][C:10]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(C)(C)C.C(C1C=C(O)C(=CC=1)C(OC)=O)(C)(C)C.[C:44]([O:48][C:49]([NH:51]CC(C)(C)CO)=[O:50])([CH3:47])([CH3:46])[CH3:45]>>[C:44]([O:48][C:49]([NH:51][CH2:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10]1[CH:19]=[C:18]([C:20]([CH3:22])([CH3:23])[CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1OC(N=C=O)C(C)(C)COC(C)(C)C
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Agent: COC(=O)c1ccc(C(C)(C)C)cc1O
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCC(C)(C)CNC(=O)OC(C)(C)C
Reaction time: 204 h

Procedure:
Using methods substantially equivalent to Example 21-C, except that the Mitsonobu reaction was allowed to proceed for 7 to 10 days, methyl 2-(3-tert-butoxy-carbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoate (10.85 g, 39%) as a pale yellow brittle foam was prepared from methyl 4-(tert-butyl)salicylate (14.72 g, 70.8 mmol) and 3-(tert-butoxycarbonylamino)-2,2-dimethylpropanol (14.37 g, 70.8 mmol).
Reaction SMILES: O[CH:2]([N:15]1[C:21](=[O:22])[C@@H:20]2[C@H:16]1[S:17][C:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=CC=1)=[N:19]2)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1.BrCC([C@H]1CCCO1)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC(C)=O.O>[NH2:19][C@@H:20]1[C:21](=[O:22])[N:15]2[C:2]([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)=[O:4])=[C:23]([C@H:24]3[CH2:29][CH2:28][CH2:27][O:38]3)[CH2:18][S:17][C@H:16]12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Agent: O=C(CBr)[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1

Procedure:
4-Methoxybenzyl (RS)-2-hydroxy-2-[(lR,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (4.103 g) in dichloromethane (15ml) and acetone (15 ml) was ring opened with 4-toluenesulphonic acid hydrate (3.33 g) in water (8 ml) and coupled to (R)-2-bromoacetyltetrahydrofuran (2.11 g) in acetone (20 ml) with potassium carbonate (0.687 g) as described in Example 6(b) for the diastereoisomeric mixture. After purification by flash chromatography, the title compound was obtained as a yellow gum (2.618 g, 49%); [α]D -10.7 (c 1.00 CHCl3).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C([N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH3:20])(C)C>C(Cl)Cl>[CH3:22][CH:21]([N:18]([CH2:19][CH2:20][CH2:20][CH2:19][NH:18][CH:21]([CH3:22])[CH3:23])[S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)NCCCCN(C(C)C)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Trifluoromethyl benzene sulfonyl chloride (0.104 m, 25.35 g) in methylene chloride (100 ml) was added dropwise to a solution of N,N'-diisopropylbutane,1,4-diamine (0.104 m, 17.86 gm) and diisopropyl ethyl amine (0.104 m, 13.40 g) in methylene chloride (500 ml). The reaction was stirred overnight. The reaction was washed with water, aqueous sodium bicarbonate and then brine and then stripped. The residue was dissolved in diethyl ether, filtered through Supercel to yield the title compound. Treatment with isopropanol/HCl provided the hydrochloric acid salt of the title compound, 14.64 gms, m.p. 175°-176.5° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[Br-].C([NH3+:13])CCC.C([O-])(=O)C.[K+].[C:19]([NH:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:34])[CH:24]=1)(=[O:21])[CH3:20].N(OCCC(C)C)=O>C(OCC)(=O)C.CCCCCC.O>[C:19]([N:22]1[C:23]2[C:32](=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:34])[CH:24]=2)[CH:33]=[N:13]1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1cc(C)c(NC(C)=O)cc1C
Reactant: CCCC[NH3+]
Agent: CC(=O)[O-]
Agent: CC(C)CCON=O
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2cnn(C(C)=O)c2cc1C
Yield: 201.8 %

Procedure:
Acetic anhydride (0.85 ml, 9.01 mmol), n-butylammonium bromide (0.0502 g, 0.156 mmol) and potassium acetate (0.587 g, 5.98 mmol) were added to a solution of methyl 4-(acetylamino)-2,5-dimethylbenzoate (0.661 g, 2.99 mmol) in ethyl acetate (5 ml), followed by adding thereto a solution of isoamyl nitrite (0.0458 g, 3.91 mmol) in ethyl acetate (2 ml), and the resulting mixture was stirred for 8 hours with heating under reflux. Water was added thereto, followed by extraction with ethyl acetate (three times), and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1). The solid thus obtained was suspended in hexane and stirred to be washed, and then it was collected by filtration and dried under reduced pressure to obtain methyl 1-acetyl-6-methyl-1H-indazole-5-carboxylate (0.0731 g, 11%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC>C1(C)C=CC=CC=1.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>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:17](=[O:19])[CH3:18])[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2cccnc12
Temperature: 70 °C
Yield: 72.6 %

Procedure:
A mixture of 8-bromoquinoline (2.0 g, 9.661 mmol), tributyl(1-ethoxyvinyl)stannane (4.19 g, 11.59 mmol), and Pd(PPh3)4 (557 mg, 0.483 mmol) in toluene (50 mL) was heated under argon at 70° C. for 24 h. The mixture was cooled to RT and extracted with EtOAc (2×25 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 30% EtOAc/petroleum ether) furnished 1-(quinolin-8-yl)ethanone (1.2 g, 7.01 mmol, 73% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.99 (1H, dd, J=2 Hz & 2.4 Hz), 8.22 (1H, dd, J=2 Hz & 6.4 Hz), 7.95 (2H, d, J=7.6 Hz), 7.59 (1H, t, J=8 Hz), 7.48 (1H, dd, J=4 Hz), 2.95 (3H, s). m/z (ESI, +ve) 172.0 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:30][C:31]([NH:33][CH3:34])=[O:32].O.Cl>CN(C=O)C.C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:30][C:31]([NH:33][CH3:34])=[O:32])[CH:20]=3)[CH2:13][CH2:14]2)=[O:8])=[CH:27][CH:28]=1
Reactant: CNC(=O)CCl
Reactant: O=C(NCCN1CCC(C(=O)c2ccc(Cl)cc2)CC1)c1cccc(O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)COc1cccc(C(=O)NCCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)c1
Temperature: 80 °C

Procedure:
The product of step (iii) above (0.10 g) was dissolved in DMF (3 ml), Cs2CO2 (0.23 g) and 2-chloro-N-methylacetamide (0.26 g) were added and the mixture heated at 80° C. for 16 hours. The mixture was cooled to room temperature, water and ethyl acetate were added and the organic phase separated. Evaporation of the solvent gave a gum which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.05 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:22])[C:18]([F:20])([F:19])[CH2:17][O:16][C:15]([NH2:21])=[N:14]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:21][C:15]1[O:16][CH2:17][C:18]([F:20])([F:19])[C@:13]([C:11]2[CH:10]=[N:9][N:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[C:23]#[N:24])[CH:12]=2)([CH3:22])[N:14]=1
Reactant: CN(C)C=O
Reactant: C[C@]1(c2cnn(-c3cccc(Br)c3)c2)N=C(N)OCC1(F)F
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@]1(c2cnn(-c3cccc(C#N)c3)c2)N=C(N)OCC1(F)F
Yield: 79 %

Procedure:
A mixture of (R)-4-(1-(3-bromophenyl)-1H-pyrazol-4-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine (20 mg, 53.9 μmol) (intermediate K7.1), zinc cyanide (3.8 mg, 32.3 μmol) and tetrakis(triphenylphosphine)-palladium(0) (6.23 mg, 5.39 μmol) was heated at 160° C. in N,N-dimethylformamide (0.5 ml) for 30 minutes in a microwave oven. Thereafter, the reaction mixture was evaporated at reduced pressure and purified by preparative HPLC. The 3-[4-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-pyrazol-1-yl]-benzonitrile (79% yield) was obtained as a light brown solid. MS (ISP): m/z=318.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]CN1C(OC)=NC2C1=NC(O[C@@H](C)CC)=NC=2N.FC(F)(F)C(O)=O.[CH3:30][C@H:31]([O:35][C:36]1[N:44]=[C:43]2[C:39]([N:40]=[C:41]([O:45][CH3:46])[NH:42]2)=[C:38]([NH2:47])[N:37]=1)[CH2:32][CH2:33][CH3:34].BrCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][N:42]1[C:41]([O:45][CH3:46])=[N:40][C:39]2[C:43]1=[N:44][C:36]([O:35][C@@H:31]([CH3:30])[CH2:32][CH2:33][CH3:34])=[N:37][C:38]=2[NH2:47]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: ClCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and 1-bromo-3-chloropropane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][N:17]=1
Reactant: COc1cnc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
0.24 g of 5-(4-chlorophenyl)-4-(3-chloro-5-methoxy-2-pyridyl)-6-methyl -2H-pyridazin-3-one and 6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.12 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.07 g of 3-chloro-5-(4-chlorophenyl)-4-(3-chloro-5-methoxy-2-pyridyl) -6-methylpyridazine (hereinafter, described as compound (10) of the present invention.).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14](Cl)Cl>S(Cl)(Cl)=O>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
4-Chlorosulphonylbenzoic acid (15 g, 68 mmol, 1 eq) was suspended in thionyl chloride (60 ml) and DCM (60 ml) and the reaction mixture heated at reflux for 2 hours. The solvent was evaporated in vacuo and ice cold MeOH (120 ml) was added to the residue. The reaction was stirred for 10 minutes in an ice bath before the addition of ice cold water (100 ml). The resulting precipitate was collected by filtration to yield the title compound as a white solid (15.3 g, 0.065 mmol, 96%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.Cl.[CH3:22][OH:23]>C(Cl)(Cl)Cl>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:17])[O:23][CH3:22])[N:8]=1
Reactant: CO
Reactant: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 62 h

Procedure:
A solution of 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (2 g.) in MeOH (15 ml.) and chloroform (35 ml.) at 0° was saturated with HCl gas and the solution allowed to stand for 62 hours at 0°. The solvent was evaporated and the residue partitioned between aqueous potassium carbonate and chloroform. The chloroform extracts were washed, dried and evaporated to give methyl 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valerimidate as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]([N:30]1[CH2:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][C:32]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:31]1=2)=[O:29]>O1CCCC1>[Cl:45][C:43]1[CH:42]=[CH:41][C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]([C:28](=[O:29])[CH2:27][NH:26][C:10](=[O:12])[CH2:9][CH2:8][NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:3])[CH3:13])[C:31]=2[CH:44]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(1,1-dimethylethoxy)carbonyl]-β-alanine (0.72 gram) in anhydrous tetrahydrofuran (20 mL) at 5° C. under a nitrogen atmosphere was added, in portions, 1,1'-carbonyldiimidazole (0.67 gram). The reaction was stirred at 5° C. for 30 minutes, and then at room temperature for 90 minutes. To the reaction was then added 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (1.00 gram), and the reaction was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was partitioned between saturated aqueous sodium bicarbonate (50 mL) and chloroform (50 mL). The layers were separated, and the aqueous layer was extracted with chloroform (50 mL), and the chloroform extracts were combined, washed with 25 mL each of saturated aqueous sodium bicarbonate, water, and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 3:1 ethyl acetate:hexane. The yield of the title compound was 1.23 grams (77%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21]CC3C=CC=CC=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2].[H][H]>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Yield: 107.6 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (20.8 g, 7.25 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and 2-propanol (50 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with 2-propanol and ether to give 4-(3-acetoxy-4methylanilino)-7-benzyloxy-6-methoxyquinazoline. A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under 1.5 atmospheres of hydrogen for 30 minutes. The catalyst was removed by filtration and the filtrate evaporated. The residual solid was triturated in ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[C:4]([N:6]([CH2:11][C:12]1[N:13]=[N:14][C:15]([NH:21][NH2:22])=[CH:16][C:17]=1[CH2:18][CH2:19][CH3:20])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[CH:28](O)=O>>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[C:4]([N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:11][C:12]1[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]2[N:14]([CH:28]=[N:22][N:21]=2)[N:13]=1)=[O:5]
Reactant: O=CO
Reactant: CCCc1cc(NN)nnc1CN(CC(C)C)C(=O)c1cc(F)ccc1F
Product: CCCc1cc2nncn2nc1CN(CC(C)C)C(=O)c1cc(F)ccc1F

Procedure:
A solution of 2,5-difluoro-N-(6-hydrazino-4-propyl-pyridazin-3-ylmethyl)-N-isobutyl-benzamide (78 mg, 0.21 mmol) in HCOOH (3 ml) is heated at 110° C. overnight. The solvent is removed in vacuo and to the residue is added EtOAc (10 ml) and saturated NaHCO3 aqueous solution (10 ml). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. Preparative TLC separation of the residue with 5% MeOH in CH2Cl2 provides the title compound as a light yellow oil. 1H NMR (CDCl3) (mixture of rotamers) 9.07 (s, 0.2H), 9.00 (s, 0.8H), 7.87 (s, 0.8H), 7.78 (s, 0.2H), 6.96-7.13 (m, 3H), 4.91 (s, 1.6H), 4.62 (s, 0.4H), 3.13 (d, 2H), 2.71 (t, 1.6H), 2.40 (t, 0.4H), 2.09-2.13 (m, 0.2H), 1.92-2.00 (m, 0.8H) 1.74-1.83 (m, 1.6H), 1.48-1.55 (m, 0.4H), 1.09 (t, 2.4H), 1.00 (d, 1.2 H), 0.96 (t, 0.6H), 0.81 (d, 4.8H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:16][O:15][CH2:14][C@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C1COCC1.O>[O:11]=[C:12]1[CH2:16][O:15][CH2:14][CH:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COC[C@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1COCC1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A mixture of oxalyl chloride (3.20 mL, 36.9 mmol) in THF (137 mL) is cooled to −78° C. under nitrogen and treated dropwise with DMSO (5.24 mL, 73.8 mmol). The mixture is stirred for 20 min at −78° C., whereupon trans-tert-butyl N-[4-hydroxytetrahydrofuran-3-yl]carbamate (5.00 g, 24.6 mmol) is added. Stirring at −78° C. is continued for 1 h. Triethylamine (18.5 mL, 133 mmol) is added and the reaction is warmed to room temperature. The reaction is stirred for 16 h, then water (100 mL) is added and the reaction is concentrated in vacuo to remove THF. The mixture is extracted with EtOAc (3×70 mL), the combined organics dried over magnesium sulfate, filtered, and concentrated to give 6.4 g of crude product as an orange oil. The crude product is purified on silica gel (220 g, 15-30% EtOAc/hexanes) to give the title compound as a yellow oil (2.20 g, 44%). GC-MS m/z 201 (M)+, 143 (M-t-Bu)+.