Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:28]=[CH:27][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29][C:30]([O:33][C:34]([NH:36][C@H:37]([C:44](O)=[O:45])[CH2:38][C:39]1[S:43][CH:42]=[CH:41][CH:40]=1)=[O:35])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:28]=[CH:27][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:44](=[O:45])[C@@H:37]([NH:36][C:34](=[O:35])[O:33][C:30]([CH3:29])([CH3:31])[CH3:32])[CH2:38][C:39]5[S:43][CH:42]=[CH:41][CH:40]=5)[CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3nc(N4CCNCC4)sc3c2)cc1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)[C@H](Cc5cccs5)NC(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Reaction time: 8 h

Procedure:
N-(3,4-dimethoxyphenyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide (1.00 g, 2.51 mmol), Boc-L-2-thienylalanine (0.68 g, 2.551 mmol), diisopropylethylamine (1.75 ml, 10.04 mmol) and HBTU (1.24 g, 3.26 mmol) were dissolved in DMF (71 ml) and stirred overnight. The resulting mixture was diluted with ethyl acetate (154 ml), washed with 1N HCl (3×77 ml), washed with brine (77 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue was chromatographed, eluting with dichloromethane/methanol (97:3) to yield (S)-tert-butyl 1-(4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate.
Reaction SMILES: Br[C:2]#[N:3].CC#N.[Cl:7][C:8]1[C:9]([NH2:17])=[C:10]([NH2:16])[CH:11]=[C:12]([Cl:15])[C:13]=1[Cl:14]>O.CO>[NH2:3][C:2]1[NH:17][C:9]2[C:8]([Cl:7])=[C:13]([Cl:14])[C:12]([Cl:15])=[CH:11][C:10]=2[N:16]=1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Reactant: N#CBr
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Nc1nc2cc(Cl)c(Cl)c(Cl)c2[nH]1
Reaction time: 2 h

Procedure:
To a stirred solution of 3.62 mL of 5M BrCN/MeCN in 35 mL of H2O, was added dropwise a solution of 3,4,5-trichloro-1,2-phenylenediamine (13a) (3.478 g, 16.446 mmol) in 35 mL of MeOH. After the addition had been completed, stirring was continued at room temperature for 2 hr. The reaction mixture was concentrated to ~ 35 mL and was washed with EtOAc (50 mL). The EtOAc phase was extracted with H2O (50 mL). The combined H2O phase was neutralized with sat. NaHCO3 solution to ~ pH 8 and the resulting suspension was extracted with EtOAc (150 mL). The EtOAc phase was washed with a mixture of sat. NaHCO3 and sat. NaCl solution (213 mL/130 mL), dried (Na2 SO4), and evaporated. The residue was dissolved in MeOH, decolorized with charcoal, and then recrystallized from MeCN to give 3.098 g (2 crops, 80%) of 13b as a slightly grey crystals. MP: 255°-258° C. MS: (El) m/e 234.9473 (100%, M+ =234.9471). 1H NMR(DMSO-d6): d 11.25 (br s, 1, 1-NH), 7.29 {s, 1, 7(4)-H}, 6.75 (br s, 2, 2-NH2). Anal. Calcd. for C7H4Cl3N3 : C 35.55, H 1.70, N 17.77, Found: C 35.72, H 1.78, N 17.89.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2occc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}-propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-6, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gives N-[1-(3-benzyl-4-oxo-3,4-dihydrofuro[2,3-d]pyrimidin-2-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([Cl:15])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+). 1H NMR (CDCl3) δ 7.00-7.40 (m, 3H), 7.60-7.90 (m, 3H), 8.70 (bs, 1H). 4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K2CO3 (359 mg, 2.6 mmol) in CH3CN (2.5 mL) as the filtrated was concentrated to give a residue which was purified by column (SiO2, CHCl3:MeOH: NH3 9:1:0.4%) to give 420 mg of N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide (85%). Purity>95% according to HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. The Raney-Ni was filtered (celite pad), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, CHCl3:MeOH: NH3 9:1:0.4%). The product was isolated as hydrochloride salt by treatment with HCl gas in diethyl ether to yield 170 mg of final product (32%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccc(F)cc1
Yield: 28.8 %

Procedure:
3.0 g (13 mmol) of 4-fluorobromobenzene, 100 ml of anhydrous diethyl ether, 12 ml (19 mmol) of 1.6 M n-butyllithium (hexane solution) and 3.8 g (19 mmol) of trimethyltin chloride were subjected to reaction, treatment and purification in the same manner as in Example 13 (a) to give 970 mg of 4-flurophenyltrimethyltin as a colorless oil (yield 22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23].[Li+].[Cl-]>CN(C=O)C.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>[CH2:23]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)[CH:22]=[CH2:21]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2ccc(OC)nc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of trifluoro-methanesulfonic acid 2-methoxy-quinolin-8-yl ester (3.07 g, 10 mmol, prepared according to WO 2006/021448), allyltributylstannane (3.8 mL, 1.25 eq.), Pd(PPh3)4 (0.29 g, 0.025 eq.) and LiCl (1.6 g, 3.75 eq.) in DMF (20 mL) was stirred at 100° C. for 3 h. After cooling to rt, the mixture was poured on water and extracted with EA. The aq. layer was extracted once more with EA and the combined org. layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 9:1) to give 8-allyl-2-methoxy-quinoline which was contaminated with stannane residues. This crude oil was dihydroxylated following General Method F using AD-mix β, was affording, after purification by CC (Hept/EA 2:1, 1:1, EA) a colourless solid (2.04 g, 87% yield).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.CO>CC(O)C.C(OCC)(=O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1nccnc1Br
Solvent: CC(C)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nccnc1NC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of methyl 2-bromopyrazine-3-carboxylate (J. Med. Chem., 1969, 12, 285) (2.2 g, 10.1 mmol) and 4-amino-1-benzylpiperidine (2.0 g, 10.5 mmol) was refluxed in 2-propanol overnight. Thin layer chromatography (10% methanol in ethyl acetate) showed the reaction was complete. The solvent was evaporated, and the crude product dissolved in chloroform (100 mL), which was washed with saturated sodium carbonate solution (20 mL), and dried over magnesium sulfate. The title compound was obtained as a gum (3.8 g). MS 327 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12](=O)[CH:13]=[CH2:14].[N:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]1[N:31]([C:28]2[CH:29]=[CH:30][C:25]([S:22]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:24])=[O:23])=[CH:26][CH:27]=2)[C:12]([CH3:11])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: C=CC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2Cl)n1-c1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
2,4-Dichlorobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-piperidinylsulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 1.50 (6H), 2.10 (3H), 2.80 (4H), 6.08 (1H), 6.35 (1H), 7.33-7.90 (7H); MS (ESI) m/z 449/451 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[ClH:19].[N:20]1([CH2:26][CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCN1CCOCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCOCC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 71 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-morpholin-4-yl)ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (71% yield). LC/MS: RT 1.97 min; m/e 412 (M+H); 1H NMR (δ, ppm): 11.85 (1H, br s), 8.36 (1H, t), 7.65 (1H, d); 7.34 (1H, s), 7.20 (1H, d), 3.93 (4H, m), 3.44 (4H, m), 3.23 (4H, m), 2.41 (2H, q), 2.33 (3H, s), 1.10 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4ccc(I)cc4)cc23)CC1

Procedure:
Following the procedure described in detail in Example 39, 0.791 gm (3.45 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 1.1 gm (3.62 mMol) 4-iodobenzenesulfonyl chloride were used to prepare 0.809 (47.3%) of the title compound as a white powder.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.C(O)C.C(OCC)(=O)C.[C:23](#[N:25])C>>[NH:7]1[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:5]([CH2:4][C:23]#[N:25])=[CH:6]1
Reactant: CN(C)Cc1c[nH]c2ccncc12
Reactant: CC#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2ccncc12
Yield: 26 %

Procedure:
Using essentially the same procedure described in Example 1, Step 5, hereinabove and employing N,N-dimethyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)methylamine as substrate and 1:2 ethanol:ethyl acetate as the chromatography eluent affords the title acetonitrile as a yellow solid, 0.160 g (26% yield), identified by NMR analysis.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6]C=1Cl.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH2:24][C:25]#N)[CH:21]=[CH:22][CH:23]=1.C[O:30][C:31](=[O:40])[CH:32](Br)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([CH2:33][CH:32]([N:4]2[C:3](=[O:15])[CH:2]=[C:25]([CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:28])([F:27])[F:16])[CH:19]=3)[CH:6]=[N:5]2)[C:31]([OH:30])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Cc2cccc(C(F)(F)F)c2)cc1=O
Yield: 70 %

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 63, starting from 4,5-dichloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and (3-trifluoromethyl-phenyl)acetonitrile and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(3-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (200.1 mg, 70% for Step 5) as a yellow solid; ES+-HRMS m/e calcd for C20H21N2O3F3 [M+H+] 395.1577, found 395.1576. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99 (br s, 2H), 1.30-1.78 (m, 7H), 1.83-2.05 (m, 1H), 2.07-2.24 (m, 1H), 3.99 (s, 2H), 5.31 (dd, J=10.6, 4.2 Hz, 1H), 6.73 (s, 1H), 7.50-7.69 (m, 3H), 7.73 (s, 1H), 7.95 (d, J=1.8 Hz, 1H), 12.97 (br s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26](SC2N=C(C)C=C(C)N=2)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].[OH-].[Na+]>O.O1CCOCC1>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:27])=[CH:37][CH:38]=1)([O-:19])=[O:18]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.55 g of trans-4-hydroxyl-L-proline and 7.5 ml of triethylamine were dissolved in 15 ml of water, and a solution of 15.95 g of S-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 35 ml of dioxane was added thereto dropwise. The resulting mixture was stirred at room temperature for 1.5 hours and allowed to stand overnight. To the reaction mixture was added 30 ml of a 2N sodium hydroxide aqueous solution under ice-cooling, and the resulting mixture was extracted with diethyl ether. The ethereal layer was washed with 20 ml of a 1N sodium hydroxide aqueous solution and combined with the alkaline aqueous layer. The combined mixture was made acidic with 100 ml of a 2N hydrochloric acid aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a 2N aqueous solution of hydrochloric acid, dried over sodium sulfate and distilled off to remove the solvent. The resulting crude crystals were washed with warm ethyl acetate to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([CH2:11][O:12][CH3:13])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[Br:35]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([CH2:11][O:12][CH3:13])=[C:10]([Br:35])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Temperature: 0 °C
Yield: 5.7 %

Procedure:
To a suspension of Intermediate AA (N-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (750 mg, 1.58 mmol)) in acetonitrile (7 ml) was added N-bromosuccinimide (365 mg, 2.0 mmol) and the mixture was heated at 60 C in a sealed vial for 1 h. After cooling to 0° C., the reaction was filtered and washed with cold CH3CN and ethyl ether (3×) to give the crude product as a solid, which was purified via flash column chromatography (95:5 v/v CH2Cl2-MeOH) to afford additional 50 mg of the title compound. 1H-NMR (DMSO-d6) δ 9.34 (s, 1H), 8.95 (d, J=3 Hz, 1H), 8.6 (m, 1H), 7.98 (s, 1H), 7.60 (d, J=3 Hz, 1H), 7.57 to 7.58 (m, 1H), 7.49 (m, 1H), 7.38 to 7.34 (m, 2H), 4.21 (s, 2H), 3.16 (s, 3H); MS [M+H]+=553; LCMS RT=3.24 min.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cccc(F)c4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(3-fluoro-phenoxy)-phenyl)-acetohydroximoyl chloride (210 mg, 0.622 mmol) described in Manufacturing Example 81-1-2 and 3-ethynyl-pyridine-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (29.0 mg, 34.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[Li]CCCC.[CH2:15]1[O:17][CH2:16]1.O>C1COCC1.CCOCC>[OH:17][CH2:16][CH2:15][C:5]1[C:4]([O:8][CH3:9])=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: COc1cccc(Cl)n1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1CCO
Temperature: 25 °C

Procedure:
To a solution of 1.0 g (7.0 mmol) of 2-chloro-6-methoxypyridine in 20 ml of dry THF cooled to -78° C. was added 10.9 ml (1.6M in hexanes, 17.4 mmol) n-BuLi under an atmosphere of nitrogen. The temperature of the mixture was allowed to raise to -40° C. before an addition of 4 ml ethylene oxide in 6 ml ether. The mixture was warmed to room temperature, 50 ml water was added and the aqueous layer was separated and extracted with 2×100 ml EtOAc. The organic extracts were combined, washed once with water, dried with Na2SO4, and concentrated in vacuo. The crude material was purified by dry column flash chromatography (hexane/EtOAc) to afford 0.22 g of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:14]([CH3:13])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
To a solution of 6-Bromoindole (1.82 g, 9 mmol) in DMF at 0° C. was added NaH (446 mg, 18 mmol). The mixture was allowed to warm to room temperature and stirred for 15 min. The reaction was then cooled to 0° C., MeSO2Cl (1.55 g, 13.5 mmol) added and the mixture stirred at this temperature for 1.5 h before being quenched with ice and diluted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a white solid (782 mg, 29% yield).
Reaction SMILES: O[CH:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5](=[O:19])[N:4]2[CH2:20][CH2:21][C@H:22]([OH:23])[C@H:3]12.C(O)(C)C>CCCCCC>[OH:23][C@@H:22]1[C@H:3]2[N:4]([C:5](=[O:19])[N:6]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=3)[CH2:2]2)[CH2:20][CH2:21]1
Reactant: N#Cc1ccc(N2C(=O)N3CC[C@H](O)[C@@H]3C2O)c2ccccc12
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#Cc1ccc(N2C[C@H]3[C@@H](O)CCN3C2=O)c2ccccc12
Yield: 24 %

Procedure:
The title compound (40 mg) was prepared from compound 42A (176 mg) by procedures analogous to those described in Example 41B. mp 226-228° C. Chiral HPLC: 99% at 7.36 min (retention time) (CHIRALPAK® AD column 4.6×250 mm; 40% isopropanol in hexane over 20 minutes, 1 mL/min, monitoring at 220 nM); MS (ES): m/z 294 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16]Br)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12
Reactant: N#CC1=C(CBr)Nc2n[nH]cc2C1c1ccccc1Cl
Reactant: c1ccc(N2CCNCC2)cc1
Product: Cl
Product: N#CC1=C(CN2CCN(c3ccccc3)CC2)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and 1-phenylpiperazine in the same manner as in Example 1076.