Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]1[S:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C@H:7]2[NH:17][C:18]([NH:20][C@@H:6]12)=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[C:44]([NH:48][CH2:49][CH2:50][CH2:51][CH3:52])[N:43]=3)=[C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:30]3[N:29]=2)=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:19]=[C:18]1[NH:20][C@H:6]2[CH2:5][S:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:41]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([NH:48][CH2:49][CH2:50][CH2:51][CH3:52])[N:43]=5)=[C:31]5[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:30]5[N:29]=4)=[CH:26][CH:27]=3)=[O:16])[C@H:7]2[NH:17]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CCCCNc1nccc(-c2c(-c3ccc(N)cc3)nn3c(NCCCC)cccc23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1nccc(-c2c(-c3ccc(NC(=O)CCCC[C@@H]4SC[C@@H]5NC(=O)N[C@@H]54)cc3)nn3c(NCCCC)cccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a cold (0° C.) solution of thionyl chloride (1 mL) was added solid d-(+)-biotin (100 mg, 0.41 mmol). The resulting mixture was warmed to room temperature and stirred for 1 hour. The excess thionyl chloride and other volatiles were removed under vacuum (<0.1 mm Hg) resulting in a solid residue. To this residue at 0° C. was added N,N-dimethylformamide (3 mL) followed by 2-(4-aminophenyl)-N-butyl-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (70 mg, 0.16 mmol) in 2 mL of N,N-dimethylformamide. The resultant solution was stirred at room temperature for 1 hour at which time the reaction appeared to be complete by analytical methods. The solution was stirred an additional 72 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (8% methanol in dichloromethane) provided 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{7-(butylamino)-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)pentanamide (30 mg, 28%) as a yellow solid. 1H NMR (DMSO-d6): δ 10.00 (s, 1 H), 7.90 (d, 1 H), 7.66 (m, 3 H), 7.46 (d, 2 H), 7.29 (t, 1 H), 6.99–6.94 (m, 2 H), 6.40 (s, 1 H), 6.32 (s, 1 H), 6.11–6.09 (m, 2 H), 6.25 (m, 1 H), 4.09 (m, 1 H), 3.47–3.06 (m, 4 H), 2.77 (m, 1 H), 2.53 (m, 1 H), 2.44 (m, 1 H), 2.97 (m, 2 H), 1.62–1.27 (m, 14 H), 0.89–0.83 (m, 6 H); MS m/z 656 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[CH2:33]([NH:40][C:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:20])[O:3][C:2]2([CH3:21])[CH3:1])[CH:13]=[N:14][CH:15]=1)=[O:19])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.100 g, 0.349 mmol) (Example 23) is dissolved in dichloromethane (2 mL). Catalytic amount of dimethylformamide (0.002 mL, 0.0262 mmol) is added to the reaction mixture and cooled to 0° C. Oxalyl chloride (0.076 mL, 0.874 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 2 h and then concentrated in vacuo. The residue obtained is redissolved in dichloromethane and benzylamine (0.114 mL, 1.04 mmol) is added. Reaction mixture is stirred at room temperature for 1 h. The mixture is washed with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichlormethane-methanol, 19:1) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid benzylamide; MS (ESI) m/z 376.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.24 (s, 3 H), 1.53 (s, 3 H), 4.62 (s, 2 H), 6.98 (s, 1 H), 7.26-7.35 (m, 1 H), 7.35-7.46 (m, 5 H), 7.57 (d, J=7.6 Hz, 1 H), 7.64-7.73 (m, 2 H), 7.74-7.84 (m, 1 H), 8.26 (dd, J=7.8, 1.5 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:19][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 34.5 %

Procedure:
To a solution of 2-amino-4-chloropyridine (2.50 g, 19.4 mmol) in N-methylpyrrolidone (20 ml) were added 3-methyl-4-nitrophenol (5.94 g, 38,8 mmol) and diisopropylethylamine (13.5 ml, 77.5 mmol), followed by stirring at 150° C. under a nitrogen atmosphere. The reaction mixture was cooled down to room temperature, and diisopropylethylamine in the mixture was evaporated under a reduced pressure. The resultant residue was partitioned between ethyl acetate (150 ml) and a 1 N aqueous solution of sodium hydroxide (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/2, ethyl acetate, then ethyl acetate/methanol=20/1) to provide the titled compound (1.64 g, 34.4%) as a brown solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:13][C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]2[C:30]#[N:31])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:13]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]3[C:30]#[N:31])=[CH:22][CH:23]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2c(C)ccnc2[nH]1
Reactant: N#Cc1cc(Cl)cn1-c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a solution of 2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (1.50 g) in dimethylformamide (15 ml) was added sodium hydride (341 mg) at room temperature under nitrogen atmosphere. The mixture was stirred for 30 minutes at the same room temperature under nitrogen atmosphere. To the mixture was added a solution of 1-(4-bromomethylphenyl)-4-chloropyrrole-2-carbonitrile (2.19 g) in dimethylformamide (15 ml). The mixture was stirred for 3 hours at room temperature. The mixture was treated with aqueous sodium bicarbonate solution, extracted twice with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (eluted by n-hexane/ethyl acetate=1/1) to yield 2-ethylthio-3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo-[4,5-b]pyridine (850 mg) as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([Sn](C)(C)C)[N:15]=3)[NH:10][C:9](=[O:21])[CH2:8]2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[CH:32][N:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:30]=2)=[N:27][CH:28]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]1[N:31]1[CH:32]=[N:33][C:29]([C:26]2[N:27]=[CH:28][C:23]([C:14]3[N:15]=[C:16]4[N:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:8][C:9](=[O:21])[NH:10][C:11]4=[N:12][CH:13]=3)=[CH:24][CH:25]=2)=[N:30]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(C1CCOCC1)CC(=O)N2
Reactant: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3)cnc2N1
Temperature: 95 °C
Yield: 39 %

Procedure:
A mixture of 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (1.2 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv), tri-o-tolylphosphine (0.2 equiv), triethylamine (3 equiv) and N,N-dimethylformamide was heated at 95° C. for 3 h under nitrogen. Concentration and chromatography purification give the desired product in 39% yield. MS (ESI) m/z 463.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:35][CH2:36]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 54.5 %

Procedure:
Following general procedure II, (R)-tert-butyl[1-(5-{[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (150 mg, 0.29 mmol) was reacted with 2-chloro6-fluro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (120 mg, 0.43 mmol) to afford the product (100 mg, 54%) as an orange-red solid: ESI MS m/z 633 [M+H]+.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:54][NH:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:59][S:56](=[O:58])(=[O:57])[NH:55][CH3:54])=[O:35])[CH2:28][CH2:27]1
Reactant: CNS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5 and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.08 g, 29%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.77-8.64 (m, 1H), 7.62-7.51 (m, 1H), 6.65-6.52 (m, 1H), 5.30-5.18 (m, 1H), 3.95-3.85 (m, 2H), 2.83-2.72 (m, 3H), 2.28-1.66 (m, 8H), 1.57-1.42 (m, 2H), 1.01-0.90 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: CN1CCCCC1.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:14]([C:36]([OH:38])=O)[CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClC(OCC(C)C)=O>ClCCl>[CH3:12][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C@@H:14]([CH2:15][S:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]([N:9]([O:10][CH3:11])[CH3:8])=[O:38]
Reactant: CNOC
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
1.96 cm3 of N-methylpiperidine are added, at a temperature in the region of 0° C., to a suspension of 1.57 g of N,O-dimethylhydroxylamine in 10 cm3 of dichloromethane. This solution is added to the reaction mixture containing 7.8 g of N-methyl-N-tert-butoxycarbonyl-S-triphenylmethyl-L-cysteine, 1.96 cm3 of N-methylpiperidine and 2.08 cm3 of isobutyl chloroformate in 20 cm3 of dichloromethane at a temperature in the region of -8° C. The reaction mixture is stirred for 2 hours at a temperature in the region of 20° C. and then washed with a 10% (w/v) aqueous citric acid solution, then with a 2% (w/v) aqueous sodium hydroxide solution and finally with a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The thick red oil obtained is purified by chromatography on silica [eluent: dichloromethane/ethyl acetate (95/5 by volume)]. 4.2 g of N-(N-methyl-2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)propionyl)-N,O-dimethylhydroxyl-amine are obtained in the form of a red oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:32][C@H:33]1[CH2:35][C@H:34]1[NH2:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:36][C@@H:34]1[CH2:35][C@@H:33]1[F:32])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccc(Cl)nc1Cl
Reactant: N[C@@H]1C[C@@H]1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1ccc(Cl)nc1Cl
Temperature: -15 °C

Procedure:
Next, this crude ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate (2.11 g, 6.62 mmol) and the para-toluenesulfonic acid salt of 2-(S)-fluoro-1-(R)-cyclopropylamine (2.45 g, 9.91 mmol) were suspended in dichloromethane (30 ml), and triethylamine (2.77 ml, 19.87 mmol) was added dropwise gradually thereto while stirring at −15° C. After completion of dripping, the reaction solution was stirred at room temperature for 15 hours. After adding ethyl acetate (100 ml) to the reaction solution, the organic layer was washed with a 10% aqueous citric acid solution (80 ml), saturated sodium bicarbonate water (80 ml), and saturated saline solution (80 ml), in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and 2.10 g (90%, 2 processes) of the title compound was thereby obtained as a yellowish-brown, oily substance (E/Z mixture). This resulting substance was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH:9][C:17]([NH:16][CH3:15])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1cccc(Cl)c1
Solvent: CC#N
Product: CNC(=O)NN(CC(=O)OC)c1cccc(Cl)c1

Procedure:
Methyl [1-(3-chlorophenyl)hydrazino]acetate (1.78 g) was dissolved in acetonitrile (20 ml) under nitrogen at room temperature. Methyl isocyanate (1.7 ml) was added to the solution which was then heated at 80° for 2 h. The solvent was removed in vacuo to give an oily residue which solidified on standing. This solid was triturated with ether and filtered to give the title compound (2.0 g), m.p. 121°-122°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[Cl:9][C:7]1[CH:6]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH3:33])=[O:31])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: COC(=O)C1CCNC(c2cc(Cl)cc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Methyl 2-(3,5-dichlorophenyl)piperidine-4-carboxylate hydrochloride (4.8 g, 14.79 mmol) was dissolved in DCM (41.5 mL) and DIPEA (6.46 mL, 36.97 mmol). Methyl chloroformate (1.374 mL, 17.74 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with 0.3 M HCl and brine. The organic layer was filtered through a phase separator and evaporated to give dimethyl 2-(3,5-dichlorophenyl)-piperidine-1,4-dicarboxylate (5.3 g) as an oil. MS m/z 346 (M+H)+
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH:35]([CH3:37])[CH3:36])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OCC2C3C(=O)N(COCC[Si](C)(C)C)N=CC=3NC=2C2C=CC(OC(F)F)=C(OC3CC3)C=2)CCC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH:35]([CH3:37])[CH3:36])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CC(C)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COC3CCC3)c2c1=O
Product: CC(C)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 67 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 13-(c) except for using 1.22 g (2.28 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-isopropoxymethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 60-(b) in place of 3-cyclobutoxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one, whereby 619 mg of the title compound was obtained as a white solid. (Yield: 67%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[N:10]([CH2:14][CH:15]=O)[CH2:11][CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][C:20]([NH2:24])([CH3:23])[CH2:21][F:22].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[CH2:1]([O:8][C:9]([N:10]1[CH2:14][CH2:15][N:24]([C:20]([CH3:23])([CH3:19])[CH2:21][F:22])[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCN(CC=O)C(=O)OCc1ccccc1
Reactant: CC(C)(N)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CC(C)(CF)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
Bis-(2-oxoethyl)carbamic acid benzyl ester (0.81 g, 3.45 mmol) and 1,1-dimethyl-2-fluoroethylamine hydrochloride (0.40 g, 3.14 mmol) were dissolved dichloroethane (50 mL), and sodium triacetoxyborohydride (1.99 g, 9.41 mmol) was added thereto. The mixture was stirred for three days at room temperature. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 30 minutes, and then extracted with methylenechloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40S, n-hexane/ethyl acetate=1/1 to ethyl acetate), to obtain the title compound (370 mg, 29%), partially including impurities, as an oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:22].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][I:22])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)C(CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 2 (392 g) in acetone (3.14 L), sodium iodide (542 g) was added. The reaction temperature went up to 29° C. from 17° C. The reaction mixture was maintained at room temperature over weekend. The mixture was filtrated and washed with MTBE. The filtrate and washings were combined and concentrated. The residue was treated with MTBE and water with a small amount of sodium thiosulfate. The organic layer was washed with water and concentrated to an oil. The oil was charged slowly into a mixture of water (2 L) and DMF (300 ml) with a small amount of seed at 5° C. The crystals were filtered and dried to give 3 (400 g, 93% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Br:18])[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Br:18])[N:14]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[N:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Brc1cc2[nH]ncc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of 5-(benzyloxy)-6-bromo-1H-indazole (5 g, 16.5 mmol) in THF (30 mL) and DCM (30 mL) is added 3,4-dihydro-2H-pyran (3 mL, 32.8 mmol) and methanesulfonic acid (1 mL, 15.3 mmol). After the reaction mixture is stirred at RT for 2 hours, EtOAc (50 mL) and saturated aqueous NaHCO3 are added. The organic phase is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the desired product (2.7 g, 42.2% yield). MS (m/z): 387.0 (M+H).