Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:17]2=[N:16][C:15]=3[NH2:26])=[C:5]([CH3:27])[CH:4]=1.C(O)C>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:17]2=[N:16][C:15]=3[NH2:26])=[C:5]([CH3:27])[CH:4]=1
Reactant: COc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step). To a round bottom flask was added 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (1 eq.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 eq.). The content was degassed (vacuum) followed by hydrogen flush (three times). The reaction mixture was stirred vigorously at room temperature overnight, under a hydrogen balloon. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until the filtrate had no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine. 1H NMR (CDCl3): δ 8.53 (d, 1H), 8.29 (d, 1H), 8.01 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.93 (d, 1H), 6.67 (d, 1H), 6.60 (dd, 1H), 5.93 (bs, 2H), 3.70 (s, 3H), 3.05-3.00 (dd, 2H), 2.93-2.88 (dd, 2H), 2.44 (s, 3H), 2.19 (s, 3H). LRMS [M+H]=358.2
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH2:9])[CH2:4][O:3]1.[F:15][C:16]1[C:21]([F:22])=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:19]([NH2:32])=[C:18]([O:33][CH3:34])[CH:17]=1>N1C=CC=CC=1>[F:22][C:21]1[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:19]([NH:32][S:10]([C:8]([CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]2)=[CH2:9])(=[O:12])=[O:11])[C:18]([O:33][CH3:34])=[CH:17][C:16]=1[F:15]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Nc1c(OC)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
(R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-ene-2-sulfonyl chloride from STEP C was dissolved in pyridine (12 mL) and 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine (2.56 g, 6.5 mmol) added. The solution was stirred at 100° C. for 2 hours and then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by flash column chromatography on silica (30% ethyl acetate/hexanes eluant) to afford (R)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-ene-2-sulfonamide (651 mg, 17%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1.[OH:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:32]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:4]=3)=[CH:39][CH:38]=2)/[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: ClCc1nc(-c2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)no2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A mixture of 5-chloromethyl-3-phenyl-1,2,4-oxadiazole (362 mg), ethyl E-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoate (789 mg, yield 92%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O.[CH:19]1C=CC=C[CH:20]=1>C(O)C.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH2:19][CH3:20])=[O:10])=[CH:16][CH:17]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccccc1Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1

Procedure:
A mixture of 560.0 g of 2-(4-bromo-phenoxy)benzoic acid in 1,940 ml of absolute benzene, 218 ml of absolute ethanol and 32.6 ml of concentrated sulfuric acid is refluxed for 32 hours, the water formed being removed in a water separator. The reaction mixture is cooled to 10° and washed, with the addition of ice, with 1,000 ml of water, 500 ml of a 2 N aqueous sodium carbonate solution and then again with 1,000 ml of water. The organic phase is separated off, dried over magnesium sulfate and evaporated at 40° under a pressure of 11 mm Hg. The residue is distilled under a high vacuum and yields ethyl 2-(4-bromo-phenoxy)-benzoate, boiling point 140°-150°/0.05 mm Hg.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17]C)=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:20][Cl:21].C([N-]C(C)C)(C)C.[Li+].[NH4+].[Cl-]>C1COCC1>[Cl-:21].[O:17]=[C:15]1[CH2:14][C@@H:11]2[CH2:10][N+:9]([C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])([CH2:13][CH2:12]2)[CH2:20]1
Reactant: COC(=O)C[C@H]1CCN([C@@H](C)c2ccccc2)C1
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)[N+]12CC[C@H](CC(=O)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A solution of (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate (25.72 g, 104.0 mmol) in THF (265 mL) is cooled under N2 in a CO2/acetone bath. Next, ICH2Cl (22.7 mL, 312.0 mmol) is added, and the mixture stirred for 30 min. A solution of 2.0M lithium diisopropylamide (heptane/THF/ethylbenzene, 156 mL, 312 mmol) is added slowly over 30 min. The internal temperature reached a maximum of −40° C. during this addition. After 1 h, sat. NH4Cl (100 mL) is added and the mixture is allowed to warm to rt. The organic layer is separated, dried (MgSO4), filtered and concentrated. The resulting foam is chromatographed (300 g SiO2, CHCl3—MeOH—NH4OH (89:10:1) followed by CHCl3—MeOH (3:1). The product fractions are pooled and concentrated to afford (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride (10.12 g) as a foam (MS (ESI+) m/z 230.1 (M+H+). This foam (10.1 g, 38 mmol) is taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) added and the mixture is hydrogenated (45 psi) overnight. The mixture is filtered and re-subjected to the reduction conditions (9.1 g, 10% Pd/C, 50 psi). After 5 h, TLC indicates the consumption of the (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride. The mixture is filtered, concentrated and triturated (minimal iPrOH) to give 3.73 g in two crops, as a solid: [α]25D=33 (c 0.97, DMSO); HRMS (FAB) calcd for C7H11NO (M+H+) 126.0919, found 126.0937. (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride
Reaction SMILES: [F:1][C:2]1[CH:3]=C(C(C)C(O)=O)C=C[CH:7]=1.B.[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1.[CH2:19]1COC[CH2:20]1>>[F:1][C:2]1[CH:7]=[C:14]([CH:18]([OH:17])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:3]=1
Reactant: CC(C(=O)O)c1cccc(F)c1
Reactant: C1CCOC1
Agent: B
Product: CCC(O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
3-Fluorophenylpropionic acid (39, 0.500 g, 2.97 mmol) was diluted in anhydrous THF (2 mL) under argon, and cooled to 0° C. Borane-THF (1 M, 4.16 mL, 4.16 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched by the addition of 1:1 THF/H2O (5 mL). When gas evolution ceased, solid K2CO3 was added until the mixture separated into two layers, which were separated. The aqueous layer was extracted with EtOAc (2×5 mL), and the combined organic layers were washed with H2O (15 mL) and sat. aq. NaCl (15 mL), dried over anhydrous sodium sulfate, and concentrated to yield the product as a clear oil (0.446 g, 97%) after drying in vacuo. 1H-NMR (500 MHz; CDCl3): δ 7.29-7.25 (m, 1 H), 7.00 (d, J=7.6 Hz, 1 H), 6.95-6.89 (m, 2 H), 3.71 (t, J=6.4 Hz, 2 H), 2.74 (t, J=7.7 Hz, 2 H), 1.95-1.89 (m, 2 H), 1.39 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[NH:18]([C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[C:19]([NH2:21])=[NH:20].[OH-].[Na+]>CO.O>[N:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[NH:23][C:22]=1[N:18]=[C:19]1[NH:21][C:9]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:21][C:19](=[N:18][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[NH:20][C:8]2([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:20]1
Reactant: O=C(C(=O)c1ccccc1Cl)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccccc1C12NC(=Nc3nc4ccccc4[nH]3)NC1(c1ccccc1)NC(=Nc1nc3ccccc3[nH]1)N2

Procedure:
Following the procedure of Example 1, 1-(2-chlorophenyl)-2-phenylethanedione (0.25 g, 1.0 mmol) and 2-guanidinobenzimidazole (0.215 g, 1.2 mmol) in methanol (12 mL) was treated with a solution of sodium hydroxide (48 mg, 1.2 mmol) in 1.2 mL of water. The title compound was isolated as pale yellow crystals (130 mg, 39% yield). MS (ESI) m/z 559 [M+H]+.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C@@H:23]([C@@H:93]([OH:111])/[CH:94]=[CH:95]/[CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108]CC)[CH2:24][O:25][C@@H:26]1[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([O:34][C@@H:35]2[O:40][C@H:39]([CH2:41][OH:42])[C@H:38]([O:43][C@@H:44]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:47]([OH:52])[C@H:46]([O:53][C@@H:54]4[O:59][C@H:58]([CH2:60][OH:61])[C@H:57]([OH:62])[C@H:56]([OH:63])[C@H:55]4[OH:64])[C@H:45]3[NH:65][C:66]([CH3:68])=[O:67])[C@H:37]([O:69][C@@:70]3([C:87]([OH:89])=[O:88])[O:75][C@@H:74]([C@H:76]([OH:81])[C@H:77]([OH:80])[CH2:78][OH:79])[C@H:73]([NH:82][C:83]([CH3:85])=[O:84])[C@@H:72]([OH:86])[CH2:71]3)[C@H:36]2[OH:90])[C@H:28]([OH:91])[C@H:27]1[OH:92])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C@H:93]([OH:111])/[CH:94]=[CH:95]/[CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH3:108])[CH2:24][O:25][C@@H:26]1[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([O:34][C@@H:35]2[O:40][C@H:39]([CH2:41][OH:42])[C@H:38]([O:43][C@@H:44]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:47]([OH:52])[C@H:46]([O:53][C@@H:54]4[O:59][C@H:58]([CH2:60][OH:61])[C@H:57]([OH:62])[C@H:56]([OH:63])[C@H:55]4[OH:64])[C@H:45]3[NH:65][C:66]([CH3:68])=[O:67])[C@H:37]([O:69][C@@:70]3([C:87]([OH:89])=[O:88])[O:75][C@@H:74]([C@H:76]([OH:81])[C@H:77]([OH:80])[CH2:78][OH:79])[C@H:73]([NH:82][C:83]([CH3:85])=[O:84])[C@@H:72]([OH:86])[CH2:71]3)[C@H:36]2[OH:90])[C@H:28]([OH:91])[C@H:27]1[OH:92])=[O:21]
Reactant: CCCCCCCCCCCCCCC/C=C/[C@H](O)[C@@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
IR spectroscopic examination on KBr pellets shows the typical band of the ester at 1750 cm-1. Chromatographic analysis of the product carried out in the same way as in Example 1 shows the presence of a unitary compound with an Rf of 0.93 and the absence of GM1 ganglioside and its internal ester (Rf 0.65 and 0.75, respectively). Hydrolysis with Na2CO3 as described in Example 1 produces the ganglioside GM1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[CH2:16]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)CC1CCCN(C(=O)OC(C)(C)C)C1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C[C@H]1CCCNC1

Procedure:
Intermediate 95 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.66 (s, 1H), 8.38 (d, 1H), 8.35 (s, 1H), 7.94 (d, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.11 (d, 2H), 6.68 (d, 2H), 4.57 (s, 2H), 3.94 (s, 2H), 3.13 (m, 2H), 2.82 (m, 6H), 2.65 (t, 1H), 2.34 (m, 2H), 1.74 (m, 4H), 1.24 (t, 3H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]4[CH:18]=[CH:19][N:20]=[C:13]4[C:12]=3[CH:21]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:24]CCOC>>[N:20]1[CH:19]=[CH:18][N:14]2[C:13]=1[C:12]1[CH:21]=[C:8]([C:7]3[C:2](=[O:24])[NH:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[CH:10][C:11]=1[O:17][CH2:16][CH2:15]2
Reactant: Fc1ncccc1-c1ccc2c(c1)-c1nccn1CCO2
Reactant: COCCOC
Agent: Cl
Product: O=c1[nH]cccc1-c1ccc2c(c1)-c1nccn1CCO2
Temperature: 80 °C

Procedure:
To a solution of 10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (100 mg, 0.4 mmol) in DME (4 mL) was added 10% aqueous HCl (4 mL). The reaction was allowed to stir and heated at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The crude was purified by Prep HPLC to provide 3-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one. LC/MS (ESI+): m/z 280 (M+H). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 8.71 (d, J=2.3, 1H), 7.72-7.50 (m, 1H), 7.47-7.21 (m, 1H), 7.15-6.86 (m, 2H), 6.29 (t, J=6.6, 1H), 4.44 (d, J=6.1, 4H).
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Yield: 78.6 %

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole (335 mg, 1.00 mmol) was dissolved in 30 ml of a 1:1 mixture of ethanol and water. To this mixture was added ammonium chloride (108 mg) and iron powder (108 mg). The mixture was then stirred at reflux for two hours, then was cooled and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 240 mg (78.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine as a tan solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), morpholine (44 uL, 44 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 43 mg (50% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.47-1.62 (m, 4 H), 1.65 (s, 9 H), 2.28-2.43 (m, 1 H), 2.92-3.04 (m, 4 H), 3.29-3.40 (m, 2 H), 3.64-3.74 (m, 4 H), 3.88-3.98 (m, 2 H), 4.51 (d, J=7.42 Hz, 2 H), 7.83 (dd, J=8.79, 1.76 Hz, 1 H), 8.03 (d, J=8.79 Hz, 1 H), 8.08 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=422.0; Anal. Calcd for C21H31N3O4S+0.90 TFA+0.20 EtOAc+0.80H2O (556.22): C, 50.96; H, 6.36; N, 7.55. Found: C, 50.94; H, 6.46; N, 7.51.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[O:11])[CH:6]=[CH:5][N:4]=1.C1COCC1.[N:27]([O-])=[O:28].[Na+].[OH-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[N:27][OH:28])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: O=N[O-]
Reactant: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nccc(C(=NO)C(=O)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-methylthiopyrimidin-4-yl)-1-(3-trifluoromethylphenyl)ethanone (4.5 g, 0.0144 mole) in acetic acid (67 mL), was added THF (54 mL) and water (9 mL). The mixture was cooled to +5° C. and a solution of sodium nitrite (1.34 g, 0.0194 mole) added dropwise while maintaining the temperature below +10° C. Upon completion of addition, the reaction was allowed to warm to room temperature for 1 hour, diluted with water (200 mL) and ethyl acetate (200 mL) and the pH adjusted to 7.5 with 3N NaOH. The layers were separated and the aqueous layer washed with ethyl acetate (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Yield 4.9 g.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][N:17]=[C:1]=[S:2])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: S=C(Cl)Cl
Reactant: CCN(CCCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCCN=C=S)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of thiophosgene (7.43 ml) in CH2Cl2 (300 ml) was added dropwise over 11/2 hours at 20° C. under a nitrogen atmosphere to a stirred solution of N-ethyl-N-(3-aminopropyl)aniline (17.8 g) and triethylamine (27.8 ml) in CH2Cl2 (500 ml). The mixture was stirred at 20° C. for a further 11/2 hours then heated under reflux for 11/2 hours. The mixture was allowed m cool washed with water, dried over MgSO4, filtered and solvent removed from the filtrate in vacuo. The product was purified by chromatography on silica gel eluting with CH2Cl2 to give N-ethyl-N-(3-isothiocyanatopropyl)aniline (72 g) as a red oil.
Reaction SMILES: CCO.[C:4]([OH:11])(=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])[CH2:13]2>CCOC(C)=O>[CH:36]1[CH:37]=[CH:38][C:33]([C@@H:24]2[N:23]([C:21]([O:20][C@@H:14]3[CH:15]4[CH2:16][CH2:17][N:12]([CH2:19][CH2:18]4)[CH2:13]3)=[O:22])[CH2:32][CH2:31][C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[CH:34][CH:35]=1.[CH2:5]([C:4]([OH:11])=[O:10])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2C1c1ccccc1
Agent: O=C(O)CCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 50 °C

Procedure:
A 6 ml portion of EtOH, 14 ml of EtOAc and 1.30 g of succinic acid were added to the thus obtained (1RS)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (3R)-quinuclidin-3-yl ester, dissolved by heating and cooled to 50° C., and then 0.003 g of seed crystal of solifenacin succinate produced in the same manner as in Example 1A was added thereto. This mixture was cooled to 30° C., and then again heated to 50° C. This was kept at 50° C. for 2 hours and then cooled to 0° C. spending 5 hours, and the precipitated crystals were collected by filtration, washed twice with 10 ml of EtOAc and then dried under a reduced pressure to obtain 2.855 g of solifenacin succinate as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)(O)[CH:13]([CH3:15])[CH3:14])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:13]([CH3:15])[CH3:14])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)C(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)=C(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.5 %

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-3-methyl-2-(pyridin-4-yl)butan-2-ol (0.668 g, 1.77 mmol) was dissolved in thionyl chloride (0.32 mL, 2.5 eq) and the solution was stirred at RT for 12 h. Volatiles were removed under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate, and the product was extracted with EtOAc (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified silica gel chromatography (100-200 mesh) eluting with 5% MeOH:DCM to obtain 0.120 g of product. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.22 (d, 2H), 7.40 (s, 1H), 7.25 (d, 1H), 7.05 (d, 1H), 7.85 (d, 2H), 5.18 (s, 2H), 4.22 (m, 2H), 3.45 (m, 2H), 2.95 (m, 2H), 2.82 (s, 3H), 2.10 (s, 3H), 1.50 (s, 3H).