Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:28][CH2:29][CH3:30])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), propan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 1), 85 (3), 73 (5), 72 (bp), 70 (7), 63 (3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1COCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccn2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 168 h

Procedure:
The title compound Is synthesized via Stille coupling analogously to the procedure of Zhang et al., Synthetic Commun. 31 (8), 1129-1139 (2001) 3-amino-5-bromo-benzotrifluoride (600 mg, 2.44 mmol), 2-tributylstannyl-pyridine (1.0 g, 2.69 mmol), and tetrakistriphenylphosphin palladium (282 mg, 0.245 mmol) dissolved in THF (10 mL) is stirred under Ar at 90° C. for 7 d. After concentrating under reduced pressure, the reaction mixture is flash chromatographed (silica gel, 2.6×46 cm, AcOEt/hexane: 1:2→2:3) to give compound of Stage 146.1 as a yellow oil: M+H=239.1; 1H-NMR (400 MHz, DMSO-d6): 8.64 (d, 5.0 Hz, 1H), 7.82 (m, 2H), 7.54/7.45 (s/s, 1H/1H), 7.36 (m, 1H9, 6.90 (s, 1H), 5.73 (s/broad, 2H); HPLC: 3.49 min (System 1); Rf (hexane/AcOEt=2:1): 1.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[CH2:15](N(CC)CC)[CH3:16].C(OC(=O)C)(=O)C.O>C(Cl)Cl>[CH3:13][O:12][C:10]1[C:6]2[C:7](=[O:9])[O:8][C:15]([CH3:16])=[N:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)oc(C)nc2c1
Temperature: 40 °C
Yield: 51 %

Procedure:
The anthranilic acid (388 mg, 1.97 mmol) prepared in Example 2 was taken up in anhydrous methylene chloride (10 mL). Triethylamine (2.36 mmol) was added followed by addition of acetic anhydride (2.36 mmol). The reaction mixture was heated at 40° C. for 18 hours. Subsequently, the reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 5,7-dimethoxy-2-methyl-3,1-benzoxazine-4-one (51% yield).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C(OCC)(=O)C>[N+:11]([C:10]1[CH:2]=[C:3]([CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:4]([NH2:6])=[O:5])([O-:13])=[O:12]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Preparation of 2-(aziridin-1-yl)-3,5-dinitrobenzamide(14) Reaction of 2-chloro-3,5-dinitrobenzamide [Palmer et al., J.Med.Chem. 1996, 39, 2518-2528] in ethyl acetate as described in Example C except that the reaction time was 2 hours, gave 2-aziridin-1-yl)-3,5-dinitrobenzamide (14) as a yellow powder, mp 200° C. [Kahn & Ross, Chem-Biol. Int., 1969-70,1, 27-47, record mp 196° C.]1H NMR [CD3)2SO] δ8 74 (d, J=2.6 Hz, 1H, H-4), 8.35(d,J=2 Hz, 1H, H-6), 8.10, 7 93 (2 br s,2H, CONH2), 2.40 (s, 4H, aziridine-H) 13NMR δ
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=O)[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1
Yield: 74.1 %

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl -1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (277 mg) in dry THF (75 ml) was treated portionwise with lithium aluminium hydride (67 mg) under nitrogen, and the suspension was then heated at reflux for 2 h. After cooling, water (10 ml) was added dropwise followed by sodium sulphate, and the mixture was then filtered. The filtrate was adsorbed onto silica and purified by FCC eluting with System A (100:8:1) to give the title compound (196 mg) as a solid, m.p. 188.5°-189.5°.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:10][OH:11])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>ClCCl>[CH3:12][C:2]([CH:10]=[O:11])([CH3:1])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(C)(C)CO
Solvent: ClCCl
Product: CCOC(=O)C=CC(C)(C)C=O
Yield: 94 %

Procedure:
Ethyl trans-4,4-dimethyl-5-hydroxypent-2-enoate (8.6 g, 0.05 mol) in 100 ml of dichloromethane was added to a stirred suspension of 70 g (0.27 mol) of chromium trioxide-pyridine complex in 900 ml of anhydrous dichloromethane. The insoluble black gum residue was washed thoroughly three times with 100-ml portions of ether. The combined organic solutions were passed through a column (3.5-cm 25-cm) of Silicagel and the solvent was removed by distillation. Distillation of the residue oil through a 20-cm Widmer column gave 8.0 g (94%) of ethyl 4-methyl-4-formylpent-2-enoate. b.p. 110 111° C./15 Torr, nD 18 1.4605. 1H NMR (CDCl3): (=1.30 [s, 6H, C(CH3)2], 1.45 (t, 3H, CH3CH2), 4.15 (q, 2H, CH2CH3), 5.85 (d, 1H, J=16 Hz, 3-H), 6.90 (d, 1H. J=16 Hz, 2-H), 9.45 (s, 1H, CHO). Anal. Calcd. for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.53; H, 8.38.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[OH-].[NH4+].[CH3:35][O:36][C:37]1[CH:43]=[C:42]([C:44]2[CH2:45][N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH:49]=2)[CH:41]=[CH:40][C:38]=1[NH2:39]>>[F:31][C:29]1[C:28]([F:32])=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[C:22]([NH:21][C:4]2[N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([C:44]4[CH2:45][N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH:49]=4)=[CH:43][C:37]=3[O:36][CH3:35])[NH:7][C:6]3=[N:8][CH:9]=[CH:10][C:5]=23)[CH:30]=1
Reactant: CCCN1CCC=C(c2ccc(N)c(OC)c2)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)c(F)cc4C(N)=O)nc(Cl)nc32)cc1
Agent: [NH4+]
Agent: [OH-]
Product: CCCN1CCC=C(c2ccc(Nc3nc(Nc4cc(F)c(F)cc4C(N)=O)c4ccnc-4[nH]3)c(OC)c2)C1
Yield: 11.9 %

Procedure:
According to General Protocol III, 4,5-difluoro-2-[4(2-{[2-(methyloxy)-4-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,5-difluorobenzamide (0.300 g, 0.630 mmol), 27% aqueous ammonium hydroxide, and 2-(methyloxy)-4-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)aniline (0.250 g, 0.950 mmol) and isolated as a yellow solid (0.040 g, 12% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.14 Hz, 3H), 1.54 (s, 2H), 1.74 (s, 2H), 2.25 (s, 2H), 2.42 (s, 2H), 3.26 (s, 2H), 3.88 (s, 3H), 6.14 (s, 1H), 6.23-6.32 (m, 1H), 6.93 (d, J=7.69 Hz, 1H), 7.02 (s, 2H), 7.76 (s, 1H), 7.91 (dd, J=1.65, 0.92 Hz, 1H), 7.97 (dd, J=11.72, 8.79 Hz, 1H), 8.12 (d, J=8.42 Hz, 1H), 8.33 (s, 1H), 9.08 (dd, J=14.65, 7.69 Hz, 1H), 11.43 (s, 1H), 12.25 (s, 1H). ESI-MS (M+H) 533. Retention time 1.75 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19](O)=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:64][C@@H:65]1[CH2:69][CH2:68][NH:67][C:66]1=[O:70]>C(Cl)Cl.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:64][C@@H:65]4[CH2:69][CH2:68][NH:67][C:66]4=[O:70])=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N[C@@H]1CCNC1=O
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 72.6 %

Procedure:
Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (850 mg, 1.84 mmol), HATU (837 mg, 2.20 mmol) and DIEA (539 mg, 0.8 mL, 4.6 mmol) in DCM (8 mL) at room temperature for 15 min, followed by addition of (R)-3-aminopyrrolidin-2-one hydrochloride (315 mg, 2.76 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL×3). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (730 mg, 73.0%). MS (m/z): 546 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.52-7.46 (m, 3H), 6.49 (s, 1H), 5.83 (s, 1H), 4.51-4.48 (m, 1H), 4.22 (d, J=17.2, 1H), 3.85 (d, J=17.2, 1H), 3.52-3.47 (m, 2H), 3.09-2.87 (m, 5H), 2.12-2.03 (m, 1H), 1.89-1.73 (m, 4H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:37])[S:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:34]=[CH:33][C:22]3=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:26]=[C:21]3[C:20](=[O:35])[C:19]=2[CH:36]=1)(=[O:13])=[O:12].C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:33]1[C:22]2=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:26]=[C:21]2[C:20](=[O:35])[C:19]2[CH:36]=[C:15]([NH:14][S:11]([N:10]([CH3:37])[CH3:9])(=[O:13])=[O:12])[CH:16]=[CH:17][C:18]=2[CH:34]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)S(=O)(=O)Nc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)S(=O)(=O)Nc1ccc2cc(Cl)c3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
N-Chlorosuccinimide (30.6 mg, 0.229 mmol) was added to N,N-dimethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide (Compound 118) (75 mg, 0.183 mmol) suspended in acetonitrile (18.3 ml) at room temperature. The resulting suspension was heated to 100° C. in a sealed vial for 24 h. After standing at room temperature for an additional 2 days, the reaction was basified with aqueous sodium hydrogen carbonate (saturated, 75 mL) and extracted with dichloromethane (2×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA, to afford the title compound as a yellow/orange solid. 1H NMR (600 MHz, CDCl3) δ 9.10 (d, 1H, J=1.8 Hz); 8.45 (d, 1H, J=2.4 Hz); 7.94 (d, 1H, J=0.6 Hz); 7.83 (s, 1H); 7.79 (d, 1H, J=2.4 Hz); 7.68 (s, 1H); 7.55 (dd, 1H, J=8.4, 2.4 Hz); 7.50 (d, 1H, J=9.0 Hz); 7.03 (s, 1H); 4.00 (s, 3H); 2.91 (s, 6H). LCMS (APCI) exact mass calc'd for [M+H]+ (C20H18ClN5O3S) requires m/z 444.1 found 444.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl.C(Cl)Cl.CO>CCO>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[CH:8]=3)=[CH:16][CH:15]=2)=[O:28])=[CH:24][CH:23]=1
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)cn2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)cc4)cc3)cn2c1
Yield: 78.2 %

Procedure:
Prepared as described in the Nitro Reduction section using N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-4-nitrobenzamide (0.10 g, 0.269 mmol) and tin (II) chloride dihydrate (0.30 g, 1.34 mmol) in EtOH (15 ml) to give the title compound (0.072 g, 78%) as a pale yellow solid after work-up and flash chromatography (15:1 DCM/MeOH).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([OH:24])=O)[N:16]=[N:15]2)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH2:1]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([NH:31][CH:29]3[CH2:30][CH2:28]3)=[O:24])[N:16]=[N:15]2)=[CH:12][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
1-{4-[(Butylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (504 mg, 1.53 mmol) obtained in Example 56b), HOBt (208 mg, 1.53 mmol, 1.0 eq.) and cyclopropylamine (0.142 ml, 1.98 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (358 mg, 1.83 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (535 mg, 1.45 mmol, 94.9%).
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:23]1([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34]/[C:3](=[C:10]3\[C:11](=[O:22])[NH:12][C:13]4[C:18]\3=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=4)/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:35][CH:36]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: O=C1Nc2cc3c(cc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1)OCO3

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 105 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 79 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:3]([N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:7]=1>CO.Cl.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[N:4][C:3]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cnc(N6CCNCC6)c(F)c5)cc34)cn2)c1
Yield: 70 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (125 mg, 0.218 mmol) was deprotected in methanol/HCl in ether (5/2.5 ml) to afford 72 mg (56.2% yield) of the titled compound after purification by prep HPLC. 1H NMR (CD3OD, 300 MHz): δ 8.646-8.640 (d, 1H), 8.56 (s, 1H), 8.419-8.415 (d, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.94-7.93 (d, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11-6.98 (m, 3H), 5.42 (s, 2H), 3.80-3.77 (m, 4H), 3.40-3.31 (m, 4H). MS: m/z=472.3 (M+1), HPLC: 98.87% in method A.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(OC(C)C)(=O)C.[OH-].[Na+]>C1COCC1.O>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A reactor was charged with 1,1,-cyclopropanedicarboxylic acid (28.3 Kg, 218 mol) and tetrahydrofuran (177 Kg) and stirred with cooling to 5° C. The reactor was charged with triethylamine (22.0 Kg, 217 mol) at a rate to maintain reaction at <10° C.; the line was rinsed with 2 Kg of THF and stirring was continued at <10° C. for 30 min. The reactor was charged with thionyl chloride (25.9 Kg, 217 mol) and the line was rinsed with an additional 2 Kg of THF and stirring was continued at <10° C. for 2 h. The reactor was charged with a solution of 4-fluoroaniline (26.6 Kg, 239 mol) in THF (70.8 Kg) and allowed to stir at <10° C. for approximately 10 h. The reactor was then charged with isopropyl acetate (246 Kg) followed by a solution of 4 wt % NaOH in water (146 Kg) and stirred for 15 min. The lower aqueous layer was drained and the organic layer washed with water. The lower aqueous layer was drained again and the organic layer washed with a solution of 20 wt % sodium chloride (141.5 Kg). The aqueous layer was drained and the organic layer distilled in vacuo to approximately 110 L. The product was treated with heptane (192 Kg) and the contents were cooled and stirred at 20° C. for 3 h. The resulting solids were filtered and washed with heptane (113 Kg) to provide crude 1-{[(4-fluorophenyl)amino]carbonyl}cyclopropanecarboxylic acid (35.5 Kg). A glass column packed with 1 Kg sand was filled with 63-200 mesh silica gel (17 Kg) and methanol (80 Kg). The crude product was dissolved in methanol (283 Kg) and passed through the silica gel bed collecting the UV active eluent. Remaining product was flushed off the silica gel with additional methanol (25 Kg). The combined fractions were stirred in a vessel and treated with water (340 Kg); the contents were stirred at 20° C. for approximately 30 min.
Reaction SMILES: O.[OH:2][CH2:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[O:2]=[CH:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: C[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Water (2.57 ml, 143 mmol) was added dropwise to a mixture of (R)-tert-butyl (1-hydroxypropan-2-yl)carbamate (17.85 g, 102 mmol) and Dess-Martin Periodinane (60.5 g, 143 mmol) in anhydrous DCM (500 ml) at rt under a nitrogen atmosphere. The reaction was allowed to stir at rt overnight before diluting with diethyl ether and filtering. The filtrate was evaporated in vacuo and the residue diluted with diethyl ether. The organic was then washed with a 1:1 mixture of 10% aq sodium thiosulfate solution: sat. sodium bicarbonate solution, followed by brine and water. The aqueous phase was then back extracted with one portion of diethyl ether, the combined organics were then dried (MgSO4) and evaporated in vacuo to give (R)-tert-butyl (1-oxopropan-2-yl)carbamate (15 g, 87 mmol, 85% yield) as a white solid.