Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CNS(C)(=O)=O)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 (0.050 g, 0.14 mmol) and triethylamine (0.0235 mL, 0.169 mmol) in methylene chloride (0.902 mL) was added methanesulfonyl chloride (13.1 uL, 0.169 mmol) dropwise. The reaction was stirred at room temperature for 1 hour. Water was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 533 as a white solid (24 mg). MS(ESI+) 434.1. 1H NMR (400 MHz, DMSO) δ 8.31 (d, J=8.2 Hz, 1H), 7.61 (t, J=6.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.06 (br, 1H), 5.76 (hept, J=6.1 Hz, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.17 (d, J=6.2 Hz, 2H), 3.43 (t, J=4.9 Hz, 2H), 2.89 (s, 3H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[C:4]([F:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:27][C:22]1[N:23]=[C:24]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[CH:10]4)=[C:4]([F:18])[CH:3]=2)[CH:25]=[C:20]([Cl:19])[N:21]=1
Reactant: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1.65 g (6.78 mmol) of 5-(4-amino-2-fluorophenoxy)-1H-indazole (from example XII) are suspended in 90 ml of water. 1.11 g (6.78 mmol) of 4,6-dichloro-2-pyrimidineamine and 0.68 ml of concentrated aqueous hydrogen chloride solution are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline with saturated sodium bicarbonate solution and extracted 3× with ethyl acetate. The organic phase is dried with sodium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][CH2:3]1
Reactant: NC1CCC(N)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC1CCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
1,4-Diaminocyclohexane (cis, trans mixture) (24.0 g, 210 mmol) and triethylamine (16.3 ml, 117 mmol) were dissolved in methylene chloride (400 ml). A solution of triphenylmethyl chloride (32.5 g, 117 mmol) dissolved in methylene chloride (100 ml) was dropwise added under ice-cooling and the mixture was stirred for 15 minutes and at room temperature for 45 minutes. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure. Water (100 ml) was added to the residue and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform/n-hexane=5/1-10/1) to give 18.4 g of 1-amino-4-(triphenylmethylamino)cyclohexane as a pale-yellow oil (25%).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH:21]=[CH:22][S:23][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2C3C(=C(F)C=CC=3)C(O)(C3C(O)=CC4OCCOC=4C=3)C2=O)C=CC=CC=1>>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH:21]=[CH:22][S:23][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2sccc2cc1O
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2
Product: O=C1C(c2cc3sccc3cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 82C and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (94%) as an off-white solid: MS (ES+) m/z 448.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([S:18]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]3[S:30][C:31]4[CH2:32][NH:33][CH2:34][CH2:35][C:36]=4[N:37]=3)=[O:28])[CH:23]([CH2:38][C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:22]1)(=[O:20])=[O:19])=[CH:12]2.C(N(CC)CC)C.[C:53](=O)([O:61]C1C=CC([N+]([O-])=O)=CC=1)[O:54][CH:55]([O:57][C:58](=[O:60])[CH3:59])[CH3:56]>C(O)C>[C:58]([O:57][CH:55]([O:54][C:53]([CH:34]1[NH:33][CH2:32][C:31]2[S:30][C:29]([C:27]([N:24]3[CH2:25][CH2:26][N:21]([S:18]([C:13]4[NH:14][C:15]5[C:11]([CH:12]=4)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=5)(=[O:20])=[O:19])[CH2:22][CH:23]3[CH2:38][C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])=[O:28])=[N:37][C:36]=2[CH2:35]1)=[O:61])[CH3:56])(=[O:60])[CH3:59]
Reactant: CS(=O)(=O)NC(=O)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CNCC2
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(=O)OC(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)NS(C)(=O)=O)sc2CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In ethanol (2 ml) was dissolved N-[[4-[(5-chloroindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]methanesulfonamide trifluoroacetate (97 mg), followed by the addition of triethylamine (0.63 ml) and 1-acetoxyethyl p-nitrophenyl carbonate (110 mg). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride was added to the residue. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1), whereby the title compound (50 mg) was obtained as a colorless foam.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>O1CCCC1>[C:35]([C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
To tetrahydrofuran was added 0.1 mole of lithocholic acid and 0.1 mole of triethylamine, and the resulting solution was maintained at a temperature below 4° C. in an ice bath. 0.12 mole of acetyl chloride was slowly added thereto, and the resulting solution was reacted for 8 hours. Thereafter, residual solvent was removed by using a vacuum distillator. A compound was extracted by using ethyl acetate, and washed with water a few times, to obtain 3α-acetylcholanic acid. To tetrahydrofuran was added 0.2 mole of 3α-acetylcholanic acid thus obtained and a slight amount of p-toluensulfonic acid. 0.21 mole of ethylvinylether was added to the resulting solution. Then, the resulting solution was reacted for 12 hours, to obtain 3α-acetylethoxyethyl lithocholate of formula 3 (yield: 70%).
Reaction SMILES: [CH:1]1([C:5]([F:18])([F:17])[C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Li+].O>O1CCCC1>[CH:1]1([C:5]([F:17])([F:18])[C:6]2[CH:16]=[CH:15][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1ccc(C(F)(F)C2CCC2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[cyclobutyl(difluoro)methyl]benzoate (synthesized by the method of WO2005/032465, 140 mg, 0.55 mmol) in tetrahydrofuran (5 mL) and methanol (112 μL, 2.76 mmol) was added lithium borohydride (60 mg, 2.75 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, and then to the reaction solution was added water at 0° C., and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude {4-[cyclobutyl(difluoro)methyl]phenyl}methanol (111 mg) as a colorless oil. The resultant was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:14]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C1NCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N1CCNC1=O
Reaction time: 8 h

Procedure:
To a solution of 2-imidazolidone in toluene with an appropriate base (e.g., triethylamine) is added a solution of an equimolar amount of lauroyl chloride in toluene. This is stirred overnight, filtered and the filtrate concentrated to give the above product.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[O:29])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(Nc2ccncc2)cc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(N(c1ccccc1)c1ccccc1)N(c1ccccc1)c1ccncc1

Procedure:
A solution of 8.51 g (0.05 mol) of N-phenyl-4-pyridinamine in 400 ml of chloroform is mixed with 11.5 g (0.11 mol) of triethylamine. To this mixture is added, dropwise with stirring, a solution of 11.6 G (0.05 mol) of diphenylcarbamic chloride in chloroform.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O-:16].[Na+]>CO>[CH3:14][O:13][C:12]1[C:3]([CH2:2][O:16][CH3:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(OC)c1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1c(OC)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a 100 mL flask containing 10.1 g (0.039 mol) of methyl 2-bromomethyl-3-methoxybenzoate in 50 mL of CH3OH, were added 19 g of a 25% wt. solution of NaOMe (4.74 g, 0.087 mol). The reaction was stirred at room temperature for 2 hours and then evaporated on a rotary evaporator to remove the CH3OH. About 200 mL of water were added to the residue and the resulting solution was extracted with CHCl3. The CHCl3 extract was dried and evaporated to yield 6.27 g of crude methyl 3-methoxy-2-methoxymethylbenzoate (77% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7-7.4 (multiple, 3H), 4.783 (s, 2H), 3.897 (s, 3H), 3.864 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:16][C:17](=[O:24])[CH2:18]/[C:19](/[C:20]([O:22][CH3:23])=[O:21])=[CH:6]\[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)CCC(=O)OC
Product: COC(=O)C/C(=C\c1cc(OC)c(OC)c(OC)c1)C(=O)OC

Procedure:
3,4,5-Trimethoxybenzaldehyde and succinic acid dimethyl ester are treated in the same manner as in Reference Example 1 to give (E)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl) -3-butenoic acid methyl ester as pale yellow syrup.
Reaction SMILES: CN(C)C1C=CC(CN[C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=CC=1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][C:9]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18]
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Reactant: NCCc1ccccc1
Product: O=C(CCCNC(=O)NCCc1ccccc1)NO

Procedure:
Compound 1 was prepared using the methodology described for the preparation of compound 2, by substituting 4-dimethylaminobenzylamine dihydrochloride with phenethylamine. 1H NMR (CD3OD) δ 7.30-7.15 (m, 5H), 3.34 (t, J=6.9 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.09 (t, J=7.5 Hz, 2H), 1.73 (m, 2H). 13C NMR (CD3OD) δ 172.7, 161.3, 140.9, 130.0, 129.6, 127.4, 42.8, 40.4, 37.7, 31.3, 27.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[CH2:13](I)[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][CH2:13][CH3:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: OCc1cc(Br)cc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of 3,5-dibromobenzyl alcohol (2.0 h, 8 mmol) in tetrahydrofuran (80 mL) was cooled to 5° C. and treated with sodium hydride (dispersion in oil 55%; 316 mg, 8 mmol). The mixture was left to warm to room temperature and stirred for 15 min. Ethyliodide (2.35 g, 15 mmol) was added and the mixture stirred for 5 h. For the working-up, the reaction mixture was evaporated, then extracted with a mixture of ethyl acetate and saturated sodium hydrogencarbonate solution. After the aqueous layer was re-extracted twice with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. There were obtained 1.15 g of the title compound (yield: 52%) as a yellow oil in sufficient purity to be engaged in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1CCC1CCCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCC1CCCN21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl 7-amino-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (Intermediate 33, 0.575 g) in pyridine (15 mL) and DCM (15 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give a pale yellow solid which was triturated with a mixture of ether and cyclohexane (1:1) to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (0.966 g)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.[ClH:29]>CC(=O)OCC>[ClH:29].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C

Procedure:
A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (5.0 g, 12.9 mmol) in 5N HCl in EA (30 mL) was stirred at room temperature overnight, then concentrated to give product as a off-white solid, which was used for next step directly.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(N(CC)CC)C>[C:18]1([C:17]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)c1ccccc1
Yield: 7 %

Procedure:
To a mixture of 5-amino-3-phenyl-1H-indazole (190 mg, 0.909 mmol) in acetonitrile (6 mL) was added benzoyl chloride (123 mg, 0.909 mmol). The solution was allowed to reflux for three hours. Triethylamine (3 drops) was added over a period of one hour while reflux continued for an additional hour. The solution was condensed and distilled water was added. The reaction mixture was extracted with ethyl acetate. The organics were dried using sodium sulfate, and condensed to give a solid. The solid was purified using chromatography (SiO2, 30–45% ethyl acetate/hexanes) to give the title compound (20 mg, 8% yield). 1H NMR (DMSO-d6) δ 13.40 (br s, 1H), 10.32 (s, 1H), 8.56 (s, 1H), 7.96 (m, 4H), 7.75 (d, 1H), 7.55 (m, 6H), 7.39 (t, 1H); ES-MS (m/z) 314 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:39][C:36]2[CH:35]=[CH:34][C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(-c2ccccn2)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(-c2ccccn2)cc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-pyridin-2-ylphenol (Tetrahedron, 1998, 54, 1289): 1H-NMR (CDCl3) δ 8.71 (1H, m), 8.56 (1H, d, J=2.8 Hz), 8.19–7.71 (8H, m), 7.41 (2H, d, J=1.8 Hz), 7.29–7.25 (3H, m), 5.36 (1H, m), 1.58 (3H, d, J=7.0 Hz), 1.57 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8]([OH:10])=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([Cl:32])[CH:31]=1)[NH:28][N:27]=[CH:26]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:32][C:30]1[CH:31]=[C:23]([NH:22][C:8]([C:7]2[CH:6]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:5][C:4](=[O:21])[NH:3][C:2]=2[CH3:1])=[O:10])[CH:24]=[C:25]2[C:29]=1[NH:28][N:27]=[CH:26]2
Reactant: Nc1cc(Cl)c2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1=C(C(=O)Nc2cc(Cl)c3[nH]ncc3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.3 %

Procedure:
The product of Example 1, Step 2 (100 mg, 0.355 mmol, 1.00 equiv), 5-amino-7-chloroindazole (59 mg, 0.355 mmol, 1.0 equiv), and EDC (82 mg, 0.427 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.059 mL, 0.427 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-80% CH3CN/H2O—NH4OH to pH 10 over 9 minutes, retention time 6.18 min) to provide 5 mg (3%) of the title compound as a white solid. MS (ES+) m/e 431 [M+H]+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CSC.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:30])=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=4)[CH:19]=3)[C:14](=[O:31])[C:13]([C:32]([O:34]CC)=[O:33])=[C:12]2[N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:10][CH2:9]1>ClCCCl.C(Cl)(Cl)Cl>[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:30])=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=4)[CH:19]=3)[C:14](=[O:31])[C:13]([C:32]([OH:34])=[O:33])=[C:12]2[N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1c(N2CCOCC2)n(C2CC2)c2cc(Cc3nc(C(C)C)cs3)c(F)cc2c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CSC
Product: CC(C)c1csc(Cc2cc3c(cc2F)c(=O)c(C(=O)O)c(N2CCOCC2)n3C2CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
A solution of aluminum chloride (266 mg, 2.00 mmol) in 1,2-dichloroethane (4 ml) was added with dimethyl sulfide (0.293 ml, 4.00 mmol) and stirred at 0° C. for 30 minutes. Then, the reaction mixture was added with ethyl 1-cyclopropyl-6-fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl)methyl]-2-morpholino-4-oxo-1,4-dihydro-3-quinolinecar boxylate (51.5 mg, 0.0999 mmol) and refluxed overnight by heating. The reaction mixture was left stand for cooling, diluted with chloroform, washed with 1 N hydrochloric acid, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by preparative TLC (chloroform:methanol=10:1) to obtain the title compound (1.3 mg, 3%).