Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]=O)=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12.[CH2:25]([C@H:27]1[C@@H:31]([N:32]=C=O)[CH2:30][C@@H:29]([NH:35][S:36]([CH:39]2[CH2:41][CH2:40]2)(=[O:38])=[O:37])[CH2:28]1)[CH3:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][NH:32][C@@H:31]2[C@H:27]([CH2:25][CH3:26])[CH2:28][C@H:29]([NH:35][S:36]([CH:39]3[CH2:41][CH2:40]3)(=[O:38])=[O:37])[CH2:30]2)=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CCC=O)cnc32)cc1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N=C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1NCCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a mixture of 3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.420 g, 1.04 mmol) and N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide (0.290 g, 1.25 mmol, prepared using OOO from Example #23 step E with NaOH) in DCE (4.00 mL) was added glacial acetic acid (0.089 mL, 1.6 mmol). The reaction mixture stirred for about 15 min at ambient temperature and sodium triacetoxyborohydride (0.331 g, 1.56 mmol) was added. The reaction was left stirring at ambient temperature for about 72 h. Saturated aqueous NaHCO3 (about 5 mL) was slowly added followed by DCM (5 mL). The layers were separated and the aqueous phase was extracted with DCM (2×5 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The remaining yellow oil was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in heptane to give N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclo-propanesulfonamide (0.330 g, 55%) as a white foam: LC/MS (Table 1, Method b) Rt=2.10 min; MS m/z: 579 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.CC(O)=O.Br.CS(C)=O>CCOC(C)=O>[NH2:11][C:9]1[S:10][C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:8]=1
Reactant: Cc1ccc(NC(N)=S)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N)sc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
(4-Methylphenyl)thiourea (2 mmol) was added to AcOH (4 ml), and the suspension was heated to 80° C. To the solution formed was added 33% HBr in AcOH (4 mmol) followed by DMSO (2.1 mmol). After stirring at 80° C. for 1 h, the reaction mixture was cooled to 50° C., diluted with EtOAc (10 ml) and filtered. The product (as HBr-salt) was taken up in H2O (5 ml) and treated with 1M aq. NaHCO3 (2 ml). Stirring was continued for 0.2 h. The precipitated aminobenzothiazole was then filtered, washed with H2O (10 ml) and dried (16 h at 45° C./20 mb); yield 67%.
Reaction SMILES: [F:1][S:2]([F:20])([F:19])([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:14](=[O:16])[CH3:15])[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=1.C(OC)(OC)OC.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.[Br-:43].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1>[Br:43][CH2:15][C:14]([C:5]1[CH:6]=[C:7]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:8]=[C:3]([S:2]([F:1])([F:17])([F:18])([F:19])[F:20])[CH:4]=1)=[O:16]
Reactant: CC(=O)c1cc(N2CCCC2)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(CBr)c1cc(N2CCCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
1-[3-(Pentafluorosulfanyl)-5-pyrrolidin-1-ylphenyl]ethanone (78 mg) was dissolved in methanol (5 ml) and admixed while stirring with trimethyl orthoformate (80 mg) and DL-10-camphorsulfonic acid (57 mg). After stirring at RT for 3 h, THF (5 ml) was added, followed by phenyltrimethylammonium tribromide (83 mg). After stirring at RT for 3 h, the mixture was left to stand overnight. Then the mixture was heated to 50° C. for 3 h and subsequently dried. The residue was taken up in ACN, admixed with 2N sulfuric acid and stirred for 30 min. Then it was admixed with water and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 9 mg of the desired compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4](C)[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[C:20]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=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>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:33]2[CH:34]=[CH:35][C:30]([C:20]3[C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[C:25]=4[CH:17]=[CH:18][CH:19]=3)=[CH:31][CH:32]=2)=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COC(=O)C(C)CSCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A solution of 3-(4-bromophenylmethylsulfanyl)-2-methylpropanoic acid methyl ester (0.427 g, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.302 g, 1.05 mmol) and Pd(PPh3)4 (0.052 g, 5 mol %) in toluene (10 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid methyl ester (312 mg, 67%) as an oil. 1H NMR (CDCl3), 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 3.79 (s, 2H), 3.71 (s, 3H), 2.76 (m, 2H), 2.56 (q, J=6 Hz, 1H). LCMS 480 (M++23).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:22])[CH:11]=[N:12][C:13]1[N:14]=[CH:15][C:16]2[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>CN(C=O)C>[I:1][C:19]1[C:17]2[N:18]=[C:13]([N:12]=[CH:11][N:10]([CH3:22])[CH3:9])[N:14]=[CH:15][C:16]=2[NH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CN(C)C=Nc1ncc2[nH]ccc2n1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ncc2[nH]cc(I)c2n1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
N-Iodosuccinimide (3.2 g, 14.2 mmol) was added portionwise to an ice-cold stirred suspension of N,N-dimethyl-N′-(5H-pyrrolo[3,2-d]pyrimidin-2-yl)-formamidine (Journal of Medicinal Chemistry, 2003, 46(14), 3060-3071, 2.68 g, 14.2 mmol) in DMF (50 mL). After stirring at ambient temperature overnight, the reaction was concentrated, dissolved in DCM (40 mL) and the product was precipitated using EtOAc (250 mL). After filtration, the pale yellow powder was collected, washed with EtOAc (2×20 mL) and dried under a vacuum overnight to afford N′-(7-iodo-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-N,N-dimethyl-formamidine (3.8 g, 85%) as a yellow powder; 1H NMR (DMSO-d6, 400 MHz) δ 12.38 (s, 1H), 8.74 (s, 1H), 8.04 (s, 1 H), 7.93 (s, 1H), 3.29 (s, 3H), 3.19 (s, 3H); ESI−MS [M+H]+=316.1.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[C:17]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]2)=[O:26])=[CH:16][C:15]=1[Cl:38].[O-2].[Ca+2]>ClCCl.CO>[NH2:13][C:14]1[C:19]2[CH2:20][C:21]([CH3:23])([CH3:24])[O:22][C:18]=2[C:17]([C:25]([NH:27][CH:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][NH:37][C:2]3[N:11]=[C:10]([OH:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[CH2:32][CH2:33]2)=[O:26])=[CH:16][C:15]=1[Cl:38]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC3CCN(CCCN)CC3)c2O1
Reactant: Oc1nc(Cl)nc2ccccc12
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC3CCN(CCCNc4nc(O)c5ccccc5n4)CC3)c2O1
Temperature: 140 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A mixture of 4.15 g of 2-chloro-4-hydroxyquinazoline, 4.57 g of 4-amino-N-[1-(3-aminopropyl)-4-piperidinyl]-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide (described in EP-0,445,862) and 0.80 g of calcium oxide was stirred for 1 hour at 140° C. The reaction mixture was dissolved in a mixture of dichloromethane and methanol. The whole was washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 90:10; CH2Cl2 /CH3OH(NH3) 88:12). The eluent of the desired fraction was evaporated and the residue was boiled in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 g (50.8%) of 4-amino-5-chloro-2,3-dihydro-N-[1-[3-[(4-hydroxy-2-quinazolinyl)amino]propyl]-4-piperidinyl]-2,2-dimethyl-7-benzofurancarboxamide; mp. 159.6° C. (comp. 12).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.C(Cl)(Cl)Cl.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CC1(C)CCCN(C)C1(C)C>CCOCC>[CH3:20][S:21]([N:10]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=1[CH3:1])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Agent: CN1CCCC(C)(C)C1(C)C
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OCC2=NCCN2S(C)(=O)=O)c1C

Procedure:
2-(2,3-Dimethylphenoxymethyl)-2-imidazoline (8.0 g; 0.0392 moles) was dissolved in dry ether (75 ml) and sufficient dry chloroform (50 ml) and the solution cooled in ice (sufficient chloroform was used to prevent precipitation of the imidazoline on cooling). Methanesulphonyl chloride (4.50 g; 0.0393 moles) was added dropwise to the cold, stirred solution. When the addition was complete pentamethylpiperidine (6.08 g; 0.0392 moles) was added and the reaction mixture heated under reflux until tlc showed that reaction was complete (~3 hrs). The reaction mixture was then concentrated under reduced pressure and the residue extracted with a water/chloroform mixture (1:1; ~100 ml). The chloroform layer was washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a residue which was recrystallised from isopropanol to give 1-methanesulphonyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, m.p. 142°-143° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH3:2]
Reactant: CCOCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride (31 0 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:9].[C:32](Cl)(=[O:34])[CH3:33].C[N+]([O-])=O>C(Cl)Cl>[C:32]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:20]([F:31])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:6]=3[F:5])[CH:12]=2)[NH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(C)=O)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 64 %

Procedure:
A slurry of aluminum trichloride (0.270 g, 2.03 mmol) was added to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.100 g, 0.254 mmol) in DCM (0.7 mL) at 0° C., and the reaction mixture was allowed to stir at 0° C. for 40 minutes. Acetyl chloride (0.0271 mL, 0.380 mmol) was added, and the mixture was allowed warm to room temperature overnight. CH3NO2 (200 μL) was added, and the reaction mixture was sonicated for 2 minutes, and allowed to stir at room temperature overnight. The reaction mixture was quenched with ice and then partitioned between aqueous sodium bicarbonate and EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (5% MeOH/EtOAc) to yield N-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (71 mg, 64%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.98-8.99 (m, 1H), 8.63-8.64 (m, 1H), 8.04 (s, 1H), 7.49-7.54 (m, 1H), 7.15-7.18 (m, 1H), 3.10-3.30 (m, 2H), 2.55 (s, 3H), 1.93-2.00 (m, 2H), 1.09-1.13 (m, 3H); m/z (APCI-pos) M+1=437.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([O:42]C)=[O:41])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].O.[OH-].[Li+].[CH3:58][S:59]([OH:62])(=[O:61])=[O:60].C(OCC)C>O1CCCC1.O>[CH3:58][S:59]([OH:62])(=[O:61])=[O:60].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([NH:27][C:28]3[N:32]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([OH:42])=[O:41])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[N:29]=3)[CH2:25][CH2:26]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COC(=O)c1ccccc1Cn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Agent: CS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccccc4C(=O)O)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-methoxycarbonylbenzyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (0.6 g, 0.8 mmol) and lithium hydroxide hydrate (0.11 g, 2.4 mmol) in tetrahydrofuran (24 mL) and water (8 mL). After 18 hours, evaporate the reaction mixture in vacuo to remove the tetrahydrofuran to obtain a solid. Collect the solid and add tetrahydrofuran (40 mL). Add a solution of methanesulfonic acid (0.24 g, 2.6 mmol) in tetrahydrofuran (3 mL). Add diethyl ether (200 mL) to give a residue. Decant the supernatant, add diethyl ether, and stir to give a solid. Collect the solid and dry in vacuo to give the title compound: mp; 161-175° C.
Reaction SMILES: S([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(O)(=O)=O.[OH-:14].[Na+]>>[OH:14][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: [OH-]
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Product: O=C(O)c1cccc(O)c1

Procedure:
The technical 3-sulphobenzoic acid melt, preferably not diluted, and the concentrated aqueous sodium hydroxide solution are pumped simultaneously into a mixing tube, the mixing tube being so designed that complete mixing takes place solely as a result of the turbulent flow produced. If desired the mixing process can also be assisted by internal fitments in the mixing tube, but this measure is not absolutely necessary. For example, 2,000 to 5,000 ml per hour of technical sulphonation melt can be mixed with corresponding quantities of sodium hydroxide solution in a mixing tube 500 mm in length and 5 mm in diameter, and can be conveyed into the reaction vessel for the subsequent pressure hydrolysis. This variant also can be carried out under normal pressure or under an elevated pressure, this elevated pressure being limited, if desired. If the initial temperatures of the components are suitably chosen, for example 150° to 180° C. for the sulphonation melt and 100° to 180° C. for the sodium hydroxide solution, a reaction temperature which is advantageous for the reaction to give 3-hydroxybenzoic acid, for example 270° to 320° C., will be reached at the end of the mixing tube. It can also be advantageous to carry out the mixing operation at a lower temperature or to limit the resulting steam pressure by blowing off steam. This process constitutes a partially continuous process in which the mixing operation in the mixing tube constitutes the continuous part of the process and the subsequent completion of the reaction in an autoclave constitutes the discontinuous part. However, since the reaction between the 3-sulphobenzoic acid and the alkali metal hydroxide becomes increasingly rapid in the upper part of the temperature range of 220° to 450° C. mentioned, it is also possible to complete the conversion into 3-hydroxybenzoic acid and thus the total reaction in a continuous form in the mixing tube itself, if the temperature is sufficiently high, for example in the region of 400° C. and if the corresponding pressure is maintained.
Reaction SMILES: [CH2:1]([C:3]12[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([CH3:15])=[CH:10][C:9]=12)[CH3:2].[C:24]([O-])(=[O:26])[CH3:25].[K+].C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C@:3]12[CH2:23][CH2:22][C:17]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:16][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:24](=[O:26])[CH3:25])[C:11]([CH3:15])=[CH:10][C:9]=12)[CH3:2]
Reactant: CCC12CCC3(CC1CCCc1cc(N)c(C)cc12)OCCO3
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC[C@]12CCC3(C[C@H]1CCCc1cc(NC(C)=O)c(C)cc12)OCCO3
Yield: 62.1 %

Procedure:
rac-(4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (24, R2=Ethyl) (0.178 g, 0.563 mmol) was dissolved in DCM (4 mL) then potassium acetate (0.138 g, 1.408 mmol) and acetic anhydride (0.115 g, 1.126 mmol) were added. After about 10 min sat. aq. NaHCO3 (3 mL) was added and the mixture was diluted with DCM (15 mL). The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-50% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-N-((4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-yl)acetamide (25, R2=Ethyl) (0.125 g, 62%); LC/MS, method 3, Rt=2.36 min, MS m/z 358 (M+H)+. 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 3.89-3.73 (m, 4H), 2.87-2.81 (m, 1H), 2.67-2.59 (m, 1H), 2.39-2.32 (m, 1H), 2.22-2.06 (m, 1H), 2.15 (s, 3H) 2.02 (s, 3H), 2.01-1.91 (m, 2H), 1.69-161 (m, 3H), 1.58-1.51 (m, 1H), 1.49-1.20 (m, 5H), 0.61 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of methyl 4-(methylamino)benzoate was cooled to 0° C. in DCM with 270 μL of Pyridine before 260 μL Methanesulfonyl Chloride was added dropwise. Reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crude material was dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-methylmethylsulfonamido)benzoate. 698 mg of methyl 4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to give 4-(N-methylmethylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 416.3 (M)+.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([O:5]C(C)(C)C)=O.[C:45]1([CH2:51]C(Cl)=O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([CH2:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:5]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[N:18][N:17]3[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cn1ncc2c(B(O)O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2cnn3C)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 1-methyl-1H-indazol-4-ylboronic acid (0.53 g, 3.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 17 h to give 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indazol-4-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=344.0 (M+1).