Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[CH3:21][Si:22](Cl)([CH2:24][CH2:25][Si:26](Cl)([CH3:28])[CH3:27])[CH3:23]>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[Si:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][Si:22]2([CH3:23])[CH3:21])[CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1cccc(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at −78° C. under N2 is treated with n-butyllithium (1.6M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at −78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at −78° C. under N2. The resulting reaction mixture is stirred at −78° C. for 50 minutes and is then treated with a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24δ.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:37][CH2:38]OC(C)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (17a) (5.6 g, 11.5 mmol), tetrakis(triphenylphosphine) palladium(0) (2.1 g, 1.8 mmol), and (2-ethenyl)tri-n-butyltin (13.5 mL, 46.2 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (17b) (4.3 g). MS m/z: [M+H+] calcd for C26H28N2O4, 433.2. found 433.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32](O)=[O:33])[CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32]([C:28]5[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccnc(C(=O)O)c1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccnc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)c1
Yield: 24.4 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.371 mmol), 4-methylpyridine-2-carboxylic acid (76 mg, 0.557 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol), triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (40 mg, 24%) was obtained as pale-yellow crystals.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([CH:37]=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([CH:9]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][OH:38])[CH:35]=3)[CH:30]=[CH:29]2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2ccn(C(c3ccccc3)c3cccc(/C=C/c4ccc5ccccc5n4)c3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2ccn(C(c3ccccc3)c3cccc(/C=C/c4ccc5ccccc5n4)c3)c2c1
Reaction time: 0.5 h

Procedure:
Solid sodium borohydride (0.11 g, 2.89 mmol) was added to a stirred suspension of 1-[α-phenyl-3-{2(E)-(quinolin-2-yl)ethenyl}benzyl]indole-6-carboxaldehyde (0.32 g, 0.69 mmol) in methanol (10 ml) and the mixture was stirred for 30 minutes giving a clear solution which was poured onto ammonium chloride solution and extracted with dichloromethane. The extract was dried and evaporated to give a solid product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH3:29])(=[N:23]C(OCC)=O)=[O:22])[CH:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:30][CH:31]([CH3:33])[CH3:32])#[N:2].ClCCl.CO>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH3:29])(=[NH:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:30][CH:31]([CH3:33])[CH3:32])#[N:2]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2C#N)c1
Solvent: ClCCl
Solvent: CO
Product: CC(C)Nc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)c(C#N)cc12
Yield: 74 %

Procedure:
According to GWP 6, the conversion of (RS)-S-[3-({[6-cyano-4-(isopropylamino)-quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (65 mg, 0.14 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 74% yield (41 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16].[OH-].[K+]>>[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)C(=O)CCc2ccccc21
Agent: [K+]
Agent: [OH-]
Product: CC1(C)C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 100 mL of HNO3 (90%) at −30° C. was slowly added 12 g 1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (Ref.: J. Am. Chem. Soc. (1993), 115, 10628). The mixture was stirred for 10 minutes and slowly poured onto 600 mL of ice water containing 120 g of KOH (more ice was added as necessary to keep the mixture cool). The mixture was extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated in vacuo. The isomers were separated iterative silica gel column using 20% ethyl acetate in hexanes followed by trituration with ethyl ether to provide 3.8 g of the higher Rf 1,1-dimethyl-6-nitro-3,4-dihydronaphthalen-2(1H)-one: 1H NMR (300 MHz, CDCl3) δ 8.1 (dd, 1H, C7-H), 8.0 (d, 1H, C5-H), 7.5 (d, 1H, C8-H), 3.2 (t, 2H), 2.7 (t, 2H), 1.5 (s, 6H), and 5.1 g of the lower Rf 1,1-dimethyl-7-nitro-3,4-dihydronaphthalen-2(1H)-one: 1H NMR (300 MHz, CDCl3) δ 8.2 (d, 1H, C8-H), 8.0 (dd, 1H, C6-H), 7.3 (d, 1H, C5-H), 3.2 (t, 2H), 2.7 (t, 2H), 1.5 (s, 6H).
Reaction SMILES: C(C1(C)[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5]C1)#N.[OH-].[Na+].O1CCCC1.C(O)(=O)[CH2:36][C:37]([CH2:42]C(O)=O)([C:39]([OH:41])=[O:40])O>C(O)C>[CH3:42][C:37]1([C:39]([OH:41])=[O:40])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:36]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(C)(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 69 %

Procedure:
A mixture of N-[2-(5-cyano-5-methyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.15 g), 2N aqueous sodium hydroxide solution (0.36 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was heated under reflux for 4 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.11 g, yield 69%) as yellow crystals from a fraction eluted with tetrahydrofuran. melting point >232° C. (decomposition).
Reaction SMILES: Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:71]=[C:70]([N+:72]([O-])=O)[CH:69]=[CH:68][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:67])[C:54]([C:56]([NH:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[O:57])=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[NH2:72][C:70]1[CH:69]=[CH:68][C:45]([O:46][C:47]2[C:52]3=[C:53]([CH3:67])[C:54]([C:56]([NH:58][CH2:59][CH2:60][N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[O:57])=[CH:55][N:51]3[N:50]=[CH:49][N:48]=2)=[C:44]([F:43])[CH:71]=1
Reactant: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 92.3 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (75 mg, 0.17 mmol) was converted to the title compound (65 mg, 92%). LCMS(ESI+) m/z 415.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](O)=[O:15])=[CH:13][C:9]=2[C:8]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:7]1)=[O:5])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:65]([NH2:74])([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([CH3:67])[CH3:66]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](=[O:15])[NH:74][C:65]([CH3:67])([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH3:66])=[CH:13][C:9]=2[C:8]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)O)sc21
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C

Procedure:
A mixture of 3-{2-[(1H-Pyrrole-2-carbonyl)-amino]-benzoylamino}-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester (198.5 mg, 0.4246 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 204 mg, 0.6369 mmol), DIEA (0.29 mL, 1.6984 mmol) and cumylamine (115 mg, 0.8492 mmol) in DMF (10 mL) was stirred at room temperature. After 2 hours the mixture was diluted with AcOEt (40 mL) and washed with saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4 and evaporated to give 495 mg of crude that was used in the next step without further purification, LC-MS: Rt 7.36; [M+H]+ 585.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([NH:2][C@@H:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][C:5]([OH:7])=[O:6])(=[O:27])=[O:28]
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of (R)-ethyl 3-amino-3-phenylpropanoate hydrochloride (5.04 g, 21.9 mmol) and naphthalene-2-sulfonyl chloride (4.97 g, 21.9 mmol) in CH2Cl2 (60 mL) was added a solution of Et3N (7.65 mL, 54.9 mmol) in CH2Cl2 (60 mL) at 0° C. over a period of 45 min. The reaction mixture was stirred at room temperature for 42 h and then washed with aqueous 1 M HCl (300 mL). The organic layer was dried (Na2SO4) and evaporated to dryness, which gave 8.05 g (96%) of S9-1 as a light pink solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1COCCO1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (107 mg, 78%), MS (ISP) m/z=459.4 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: O[C:2]1[O:3][C:4]2[C:9]([C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:20].N1C=CC=CC=1.[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28]>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:10](=[O:19])[C:9]3[C:4](=[C:5]([CH3:20])[C:6]([O:30][C:27](=[O:29])[CH3:28])=[CH:7][CH:8]=3)[O:3][CH:2]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c(=O)c(-c3ccc(O)cc3)c(O)oc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1C
Temperature: 25 °C

Procedure:
Hydroxy-3-(4-hydroxy-phenyl)-8-methyl-chromen-4-one (35.18 g) were combined into a round bottom flask (1 L). Pyridine (38 ml, 2 equivalents) and acetic anhydride (576 ml, 47 equivalents) were added to the round bottom flask while stirring at room temperature. The reaction was monitored by HPLC and was completed instantaneously. There was a change in colour observed, the reaction mixture was dark brown initially and went bright orange with tan brown floccular particles upon stirring. The reaction mixture was poured into chilled, distilled H2O (4 L) and was left stirring at room temperature for 30 minutes. An off-white solid was collected by suction filtration. 1HNMR of the solid in d-CDCl3 indicated it was Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-4H-chromen-7-yl ester with >95% purity The solid was dried on a freeze dryer for 24 hours. When dry, the solid was weighed (31.80 g, 69%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[O:15][CH:14]=[N:13][C:12]=3[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[N:13]=[CH:14][O:15][C:11]=2[C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[S:3][C:4]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(-c2ncoc2-c2ccc3nc(Br)sc3c2)cc1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ncoc2-c2ccc3nc(NCCN4CCOCC4)sc3c2)cc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of 2-bromo-6-(4-(4-fluorophenyl)oxazol-5-yl)benzo[d]thiazole (0.030 g, 0.080 mmol, 1.0 eq.) and 4-(2-aminoethyl)morpholine (0.073 mL, 0.556 mmol, 7.0 eq.) in THF (1.5 mL) was mechanically shaken at 54° C. overnight. After cooling to room temperature, the solution was concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(4-(4-fluorophenyl)oxazol-5-yl)-N-(2-morpholinoethyl)benzo[d]thiazol-2-amine as a light yellow solid (0.0182 g, 54% yield). LC/MS (MH)=425.17.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:23][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6](=[O:7])[NH:8][C:9]2=[O:10]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])C(=O)NC3=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-chloro-5-nitrophthalimide (1.05 g, 4.4 mmol), methyl 2-(3-chloro-4-hydroxyphenyl)acetate (821 mg, 4.4 mmol) and potassium carbonate (1.34 g, 9.7 mmol) in 10 mL of DMSO was allowed to stir at 25° C. for 22 h. Upon completion, the mixture was added to 50 mL of water. The resulting mixture was extracted with ethyl acetate (2×30 ml,). The combined extracts were washed with water (2×30 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on a silica gel column using 20% EtOAc/hexane as the eluent to give methyl 2-(3-chloro-4-(6-nitro-1,3-dioxoisoindolin-5-yloxy)phenyl)acetate (30.1). MS ESI (pos.) m/e calcd for (M+H)+ 391.0. found 391.0.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>C(O)C.O>[CH3:11][C:9]([CH3:12])([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:7])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (8.8 mmol, 3.79 g) in ethanol (20 mL) was added aqueous 1.0 N sodium hydroxide (17.57 mL) at room temperature. The mixture was stirred for 2 h at room temperature. Then, the mixture was diluted with water (50 ml) and the ethanol was removed under reduced pressure. The aqueous solution was washed with diethyl ether (100 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (200 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 3.44 g (94% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as a light brown foam solid. ES-HRMS m/e calcd for C21H27N3O6 (M+Na) 440.1792, found 440.1792.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][O-:16].[Na+]>CO>[F:1][C:2]1[C:3]([F:14])=[C:4]([O:16][CH3:15])[C:5]([F:12])=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: CO
Product: COc1c(F)c(F)c([N+](=O)[O-])c(F)c1F
Yield: 71.9 %

Procedure:
50 g of pentafluoronitrobenzene was dissolved in 400 ml of dry methanol. Thereto was dropwise added, with ice-cooling, a solution of 13.95 g of sodium methoxide dissolved in 50 ml of dry methanol. A reaction was allowed to take place at room temperature for 2 hours. The reaction mixture was concentrated to a volume of about ⅓ under vacuum. The residue was poured into 500 ml of water. The organic layer was extracted with 300 ml of ether. The ether layer was washed with an aqueous sodium chloride solution and dried over MgSO4. The resulting solution was subjected to vacuum distillation to remove the solvent. The residue was subjected to vacuum distillation (96 to 97° C./0.35 mmHg (47 Pa)) to obtain 38 g of 2,3,5,6-tetrafluoro-4-methoxynitrobenzene (yield: 72%).
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.[C:22]1([C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N:5]12[CH2:6][CH2:7][CH:8]([CH2:9][CH2:10]1)[C@@H:3]([O:2][C:1]([N:29]1[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:28]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])[CH2:4]2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@H]1CN2CCC1CC2
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1

Procedure:
The above mentioned step (b) comprises treating the reaction mixture comprising (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) of step (a) with (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (V) in an organic solvent and in an inert atmosphere at temperature of −20 to 50° C. to obtain (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (Solifenacin) of formula (I).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[CH3:14][N:13]([CH3:15])[C:11](=[O:12])[C:10]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[NH:8][C:6]1[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)[N:7]=1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 12 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 12% yield (pale yellow oil that solidifies on standing) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.28 (s, 1H), 8.15 (d, 1H, J=8.2 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.02 (t, 1H, J=7.4 Hz), 6.81 (s, 1H), 3.50 (s, 2H), 3.09 (s, 3H), 2.96 (s, 3H), 2.49 (bs, 8H), 2.30 (s, 3H); MS (ESI): 514.2 [M+H]+.