Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH:28]=[N:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][C:18]([CH3:24])=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: O=C1N=CCO1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)nc1C
Yield: 29.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 176 and oxazolin-2-one (104 mg), the title compound (118 mg) was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[C:20]([Cl:26])[C:21]([C:23]([NH2:25])=[O:24])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:27][CH3:28])=[CH:10][CH:9]=1)(=O)=O.[CH3:29][NH2:30]>O>[Cl:26][C:20]1[C:21]([C:23]([NH2:25])=[O:24])=[CH:22][C:17]2[N:16]=[C:15]([CH2:27][CH3:28])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][NH:30][CH3:29])=[CH:13][CH:12]=3)[C:18]=2[CH:19]=1
Reactant: CN
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Solvent: O
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC)cc1
Yield: 60 %

Procedure:
A mixture of 2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl methanesulfonate (step 1, 304 mg, 0.72 mmol), a solution of methyl amine (40% in methanol, 10 ml) and water (5 ml) in a sealed tube was heated overnight at 100° C. The reaction mixture was partitioned between dichloromethane (30 ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with brine (50 ml) and dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with dichloromethane/methanol (10:1) to afford 154 mg (60%) of the title compound as yellow solids.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9](Br)=[C:8]([CH3:13])[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH3:15])[CH:6]=1)=[O:4].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO.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.[Pd]>[CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)=[C:8]([CH3:13])[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH3:15])[CH:6]=1)=[O:4]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Temperature: 75 °C
Reaction time: 72 h

Procedure:
To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid methylamide (preparation 9, 240 mg, 0.641 mmol), 2-(trifluoromethyl)pyridine-4-boronic acid (148 mg, 0.78 mmol), palladium (0) tetrakis(triphenylphosphine) (79 mg, 0.068 mmol) in acetonitrile (4 mL) is added 2 M aqueous K2CO3 solution (0.60 mL, 1.20 mmol). After stirring for 72 h at 75° C., the reaction mixture is diluted with methanol and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 48 mg (17% of theory); ESI mass spectrum: [M+H]+=441; Retention time HPLC: 0.78 min (Z011_S03).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:20]([NH2:22])=[O:21]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:12]([NH:22][CH:20]=[O:21])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC=O
Reactant: O=C1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: O=CO
Product: O=CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 162.5 °C

Procedure:
(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone (1.2 g) was added formic acid (3 mL) and formamide (3 mL). The reaction mixture was heated to 160-165° C. for 15 h under nitrogen atmosphere. The reaction mixture was cooled to rt and decanted the solvent. The residue solids was passed through flash column using EtOAc:Hexane (3:7 to 1:1) to give and (1R,4R)—Norsertralaine formamide (400 mg, first spot), and (1S,4R)—Norsertraline formamide (360 mg). 1H NMR of the first product [(1R,4R)-isomer]: (CDCl3) δ 1.80-2.10 (m, 3H), 2.10-2.20 (m, 1H), 4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H), 6.10-6.20 (m, 1H), 6.80-6.90 (M, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m, 5H), 8.22 (s, 1H). M+320. 1H NMR of the second product [(1S,4R)-isomer: δ 1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m, 1H), 5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28 (s, 1H). Mass Spec. M+320.
Reaction SMILES: [N:1]1([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:13][CH:14]=[CH2:15])[C:11]#[N:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC>[N:1]1([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:13][CH:14]=[CH2:15])[CH2:11][NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: C=CCC(C#N)(CC=C)n1ccc2cccnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCC(CN)(CC=C)n1ccc2cccnc21

Procedure:
4 g of the compound of stage 1, dissolved in 40 ml of ether, are added to a suspension of 0.96 g (0.0253 tool) of LiAlH4 in 100 ml of ether. The mixture is heated to reflux for 3 hours. It is cooled and 5% sodium hydroxide is added at room temperature, settling is allowed to take place, the aqueous phase is washed with ether, the ether phases are dried over sodium sulphate and filtered and the filtrate is evaporated. A liquid compound is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][C@H:11]([CH3:14])[CH2:12][OH:13])[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[OH-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>CCOC(C)=O.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]([O:10][C@H:11]([CH3:14])[CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:3]=1
Reactant: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
A solution of Intermediate 151b (112 mg, 0.39 mmol) in EtOAc (2.1 mL) was treated with aqueous 1N NaOH (0.7 mL, 0.70 mmol) then 2,2,2-trichloroethyl chloroformate (0.056 mL, 0.41 mmol) and the mixture was stirred at RT for 2.5 h. The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate (0.015 mL, 0.11 mmol) and stirred at RT for a further 1 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red gum (195 mg). The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound as a pale golden gum (134 mg, 74%). LCMS (Method 3): Rt 4.15 min, m/z 464.2, 466.2 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4](Br)[C:3]=1[NH:11][C:12]([NH2:14])=[S:13].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[NH2:14][C:12]1[S:13][C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([Br:1])[C:3]=2[N:11]=1
Reactant: N#Cc1cc(Br)c(NC(N)=S)c(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(Br)c2nc(N)sc2c1
Temperature: 25 °C

Procedure:
A reaction mixture of (2) compound (1.3 g, 3.66 mmol), CuI (70 mg, 0.366 mmol, 0.1 eq.), 1,10-phenanthroline (70 mg, 0.366 mmol), and Cs2CO3 (1.8 g, 5.5 mmol, 1.5 eq.) in dioxane (20 mL) was stirred under reflux for 2 h under Ar. After cooling to room temperature, water (100 mL) was added; solid was filtered, washed with water (100 mL×3) followed by ether (50 mL×3). The solid was dried in vacuo at room temperature overnight, to provide 1 g (quantitative yield) of the desired product (3). 1H-NMR-(400 MHz, CDCl3)
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:17]2[C@@H:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19][CH2:18]2)=[O:9])[CH:3]=1
Reactant: C1CCC2NCCCC2C1
Reactant: O=C(O)c1csc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
5-Bromothiophene-3-carboxylic acid (0.5 g, 2.4 mmol) was dissolved in acetonitrile (10 mL) and triethylamine (7.1 mmol). Decahydroquinoline (3:2 mixture of cis- and trans-isomers; 4.8 mmol) and HATU (2.4 mmol) were added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in DCM and washed with water. After drying with anhydrous magnesium sulphate, the solution was filtered and evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white crystalline solid (0.39 g). LCMS m/z 330.11 [M+H]+ RT=4.07 min (Analytical Method 4).
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:37])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH2:12][CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>C1COCC1>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:37])[C:16]([N:19]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:29])=[CH:17][N:18]=[C:13]2[C@@H:12]([CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Nc1ccccc1)[C@@H]1CCc2ncc(N(Cc3ccccc3)C(=O)OCc3ccccc3)c(=O)n21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1ccccc1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a solution of 112a (101.6 mg, 0.205 mmol) in 1 mL THF at −78° C., was added 1N LiHMDS in THF (0.431 mL, 0.431 mmol). The mixture was stirred at −78° C. for 10 min, then t-butyl bromoacetate (30.3 μL, 0.205 mmol) was added, dropwise. The mixture was stirred at −78° C. for 5 h, then quenched with sat. NH4Cl. The mixture was diluted with EtOAc and washed with sat. NH4Cl and brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography to afford 110.7 mg (89%) of 112b. 1H NMR (300 MHz, CDCl3) δ9.38 (br s, 1H), 7.63 (br s, 1H), 7.45 (d, J=8.1, 2H), 7.33-7.17 (m, 12H), 7.02 (t, J=7.3, 1H), 5.17-5.11 (m, 3H), 4.84 (br s, 1H), 4.69 (br s, 1H), 3.62-3.51 (m, 1H), 2.84 (d, J=6.9, 2H), 2.79-2.67 (m, 1H), 2.40 (br s, 1H), 1.43 (s, 9H); MS (ESI) 609.2 (M+H+), 631.2 (M+Na+), 607.2 (M−H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:34]([CH3:36])[C:32]([CH2:31][NH:30][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:27])[F:29])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])=[O:33]
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 37.5 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (45.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 508; and 1H NMR (DMSO-d6, 400 MHz): δ 8.19 (1H, br. s), 7.88 (1H, br. s), 7.68 (1H, br. s), 7.55 (1H, br. s), 7.34-7.24 (2H, m), 7.13 (1H, m), 4.19-4.16 (2H, m), 4.12-4.10 (2H, d), 3.03 (3H, s), 2.88 (3H, s), 1.31-1.27 (3H, t), —NH proton signal was not observed.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]>CN(C=O)C>[CH3:5][O:6][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]
Reactant: C1CCOC1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OC
Temperature: 80 °C

Procedure:
To a mixture of methanol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water to give 4-i-propyl-phenyl sulfamic acid-[6-methoxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg). tR=5.08 min, (LC); [M+H]+=522.45 (ES+).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:13].CN(C=O)C>O>[Br:1][C:18]1[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: CCOc1cc(-c2ccc(F)cc2)ccc1C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(F)cc2)c(Br)cc1C(=O)OC
Yield: 188.7 %

Procedure:
Dibromoisocyanuric acid (3.28 g) was added to a mixture of methyl 3-ethoxy-4′-fluorobiphenyl-4-carboxylate (5.92 g) and DMF (40 mL), and the resultant mixture was stirred overnight at room temperature. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.62 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=O)(C)(C)C.[C:24]([N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH:30]([CH3:35])[C:29]1=[O:36])([CH3:27])([CH3:26])[CH3:25]>>[NH2:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:29](=[O:36])[C@H:30]1[CH3:35])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC1NCCCN(C(C)(C)C)C1=O
Product: C[C@@H]1C(=O)N(C(C)(C)C)CCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared from (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid and 1-tert-butyl-hexahydro-3-methyl-2H-1,4-diazepin-2-one by the method described in Example 3, Step C and D. LC/MS 400.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1c(F)ccc2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cc2c(CO)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of methyl 5-fluoro-2-methyl-2H-indazole-4-carboxylate (4.10 g, 19.7 mmol) in tetrahydrofuran (197 mL) was slowly added a solution (1 M, 59.1 mL, 59.1 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (3.30 g, yield 93%).
Reaction SMILES: [CH:1](=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=1)[C:23]#[N:24]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:23]([C:22]1[CH:25]=[C:18]([C:3]#[C:2][CH:1]=[C:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH:19]=[N:20][CH:21]=1)#[N:24]
Reactant: N#Cc1cncc(Br)c1
Reactant: C#CC=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cncc(C#N)c2)CC1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of Compound 2b (0.5 g, 2.26 mmol), 5-bromonicotinonitrile (0.511 g, 2.26 mmol), bis(triphenylphosphine)palladium(II)dichloride (80 mg, 0.05 mmol), CuI (43.1 mg, 0.1 mmol) in anhydrous and degassed triethylamine (12.6 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 4:96 to 30:70) affording the title product (0.731 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]2)[C:20]1=[O:39].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:31]4=[CH:32][C:33]5[O:37][CH2:36][O:35][C:34]=5[CH:38]=[C:30]4[O:29][CH2:28]3)[C:20]2=[O:39])=[CH:5][CH:4]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CSc1ccc(CBr)cc1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CSc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(methylthio)benzyl bromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (86%) as a colorless solid: mp 128-130° C.; 1H NMR (300 MHz, DMSO-d6) δ7.28-7.19 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.68 (s, 1H), 6.14 (s, 1H), 5.89 (d, J=1.9 Hz, 2H), 4.87-4.79 (m, 3H), 4.67 (d, J=9.3 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.3, 155.9, 148.8, 142.6, 142.2, 137.8, 133.3, 132.1, 129.3, 128.4, 126.6, 124.2, 123.6, 120.1, 109.9, 103.3, 101.9, 93.8, 80.4, 57.9, 43.2, 15.1; MS (ES+) m/z 418.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[N:14]=[N:15][N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:24][C@H:25]1[C@@H:29]([CH2:30][CH3:31])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1)(=[O:3])[NH2:2].Cl.O1CCOCC1>ClCCl>[CH2:30]([C@H:29]1[CH2:28][NH:27][CH2:26][C@H:25]1[NH:24][C:5]1[C:6]2[N:7]([CH:10]=[C:11]([C:13]3[N:14]=[N:15][N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=3)[CH:12]=2)[N:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3])[CH3:31]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn(-c4ccccc4)nn3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn(-c4ccccc4)nn3)cc12
Temperature: 25 °C
Yield: 106.4 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (41 mg, 0.079 mmol) in dichloromethane (1 mL) was added 4N HCl in 1,4-dioxane (0.198 mL, 0.794 mmol). The solution was stirred at room temperature. After stirring 2 h, the reaction is complete. Concentration afforded a tan solid as the hydrochloride salt of the title compound (35 mg, 99% yield). MS (ES+) m/z: 417.1 (M+H). LC retention time: 2.776 min (analytical LCMS Method J).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][OH:16])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=NOCc1ccccc1)c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=NOCc1ccccc1)c1cccc(CO)c1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 9.92 g (39.17 mmol) of 3-(1-(benzyloxyimino)ethyl)benzaldehyde in 70 ml of dry methanol and 70 ml of dry tetrahydrofuran was added 1.81 g (43 mmol) of sodium borohydride portionwise with ice-cooling, and the mixture was stirred for 2 hours with ice-cooling. Further, 0.30 g of sodium borohydride portionwise was added thereto with ice-cooling, and the mixture was stirred for 2 hours with ice-cooling. The reaction mixture was poured into 500 ml of an about 5% aqueous solution of ammonium chloride, and the mixture was extracted with tert-butyl methyl ether. The organic layer was dried and concentrated to obtain 9.64 g (37.8 mmol) of 3-(1-(benzyloxyimino)ethyl)benzylalcohol.