Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([O:14][C:15]([NH:17][CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([O:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[Br-:1].[C:6]([O:5][C:3](=[O:4])[CH2:2][N+:24]12[CH2:25][CH2:26][CH:27]([CH2:28][CH2:29]1)[C@@H:22]([O:21][C:19](=[O:20])[CH:18]([NH:17][C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:23]2)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[N+]12CCC(CC1)[C@@H](OC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1)C2
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Tert-butyl 2-bromoacetate (29.5 μl, 0.20 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C1) (72 mg, 0.20 mmol) in acetonitrile (3 ml). The reaction was stirred at RT overnight. The product was collected by suction filtration and then purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to get (3R)-1-(2-tert-butoxy-2-oxoethyl)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-azoniabicyclo[2.2.2]octane bromide (97 mg; 87% yield).
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@@H:17]([CH2:18][O:19][CH3:20])[C@@:16]3([CH3:35])[C:21]3[CH:30]=[CH:29][C:28]4[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=4[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:36].[CH3:37][C:38]12[C:44]([CH3:46])([CH3:45])[C:41]([C:47]([O:49][CH2:50][C@@H:51]3[C@H:53]([CH2:54][O:55][CH3:56])[C@:52]3([CH3:71])[C:57]3[CH:66]=[CH:65][C:64]4[C:63]([CH3:68])([CH3:67])[CH2:62][CH2:61][C:60]([CH3:70])([CH3:69])[C:59]=4[CH:58]=3)=[O:48])([CH2:42][CH2:43]1)[O:40][C:39]2=[O:72].COCC1[C@@H](CO)C1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.CCOC(C)=O>CCCCCC>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@H:17]([CH2:18][O:19][CH3:20])[C@@:16]3([CH3:35])[C:21]3[CH:30]=[CH:29][C:28]4[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=4[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:36].[CH3:37][C:38]12[C:44]([CH3:45])([CH3:46])[C:41]([C:47]([O:49][CH2:50][C@@H:51]3[C@@H:53]([CH2:54][O:55][CH3:56])[C@:52]3([CH3:71])[C:57]3[CH:66]=[CH:65][C:64]4[C:63]([CH3:68])([CH3:67])[CH2:62][CH2:61][C:60]([CH3:70])([CH3:69])[C:59]=4[CH:58]=3)=[O:48])([CH2:42][CH2:43]1)[O:40][C:39]2=[O:72]
Reactant: COC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC[C@@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COCC1[C@@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 36 %
Yield: 36 %

Procedure:
Following a procedure similar to that for the preparation of Intermediates 8a and 9a while using Intermediate 7a as the starting material and 10% EtOAc in hexane as normal phase HPLC eluent afforded Intermediate 10a (46 mg, 36% yield) and Intermediate 11a (45 mg, 36% yield) from 7a as colorless oils:
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[C:1]1([CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH3:19])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1CCCC(O)C1c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: COC(=O)CC1CCCC(O)C1c1ccccc1
Yield: 1852.5 %

Procedure:
A solution of 0.53 g (2.26 mmole) of 2-(SR)-phenyl-3-(SR)-hydroxy-(SR)-cyclohexylacetic acid in 35 mL of methanol was treated with 22 mg (0.11 mmole) of p-toluenesulfonic acid monohydrate and the mixture was heated at reflux for 27 hr. The mixture was cooled, treated with 0.02 mL of triethylamine and concentrated in vacuo. The residue was purified by flash chromatography on 67 g of silica eluting with 1.6 L of 8:1 hexanes:ethyl acetate to give 0.506 g (90%) of an oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:7][CH2:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)([CH3:6])[CH3:5].[H-].[Na+]>CS(C)=O.O>[Br:15][C:13]1[CH:12]=[N:11][C:10]2[NH:16][C:3](=[O:2])[C:4]([CH3:6])([CH3:5])[NH:7][CH2:8][C:9]=2[CH:14]=1
Reactant: COC(=O)C(C)(C)NCc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)NCc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(2-amino-5-bromo-pyridin-3-ylmethyl)amino]-2-methylpropionic acid methyl ester (2.63 g, 8.71 mmol) in DMSO (100 mL) was treated with NaH (60% dispersion in mineral oil, 0.35 g, 8.7 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (200 mL) and then extracted with EtOAc (5×150 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2,/MeOH, 99:1 to 98:2) gave (0.79 g, 33%) as an off-white solid: MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:17]1([NH:23][C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:30]([C:29]5[CH:32]=[CH:33][C:26]([C:24]([NH:23][C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[O:25])=[CH:27][CH:28]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:30]1[C:29]1[CH:28]=[CH:27][C:26]([C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(-c4ccc5nc(-c6ccc(C(=O)Nc7ccccc7)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 261 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C40H28N6O2: 625.23; found: 625.53.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1.BrCCCN1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:21]=[C:20]1[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](=[O:26])[N:1]1[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1
Reactant: N#CC1CCN(CCCN)C1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
A suspension of 3-pyrrolidinecarbonitrile (302) (Swidinsky, J., et al., J. Pharm. Sci. 1967, 56, 192-196) (4.5 g, 15.6 mmol), N-(3-bromopropyl)phthalimide (3.48 g, 13.0 mmol), and K2CO3 (2.16 g, 15.6 mmol) in DMF (20 mL) was stirred at 100° C. for 1.5 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (50 mL) and EtOAc (50 mL). The organic fraction was extracted with 1 M HCl (2×50 mL) and the acidic fraction washed with Et2O (2×20 mL). The acidic fraction was made basic with dilute aqueous NH3 solution and the alkaline solution was extracted with DCM (3×25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give phthalimide 303 (1.70 g, 46%) as a colourless oil: 1H NMR δ 7.82-7.87 (m, 2H, Harom), 7.69-7.74 (m, 2H, Harom), 3.75-3.79 (m, 2H, CH2), 2.87-2.93 (m, 2H, CH2N), 2.52-2.60 (m, 5H, CH2, CH2N, CH), 2.06-2.15 (m, 1H, CH2), 1.96-2.04 (m, 1H, CH2), 1.87 (p, J=7.0 Hz, 2H, CH2); 13C NMR δ 168.4 (2), 133.9 (2), 132.2 (2), 123.1 (2), 122.1, 57.2, 52.6 (2), 36.3, 29.1, 27.2, 26.1; HRMS (FAB+) calcd for C16H17N3O2 (M+) m/z 283.1321, found 283.1318.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([S:13][CH:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[CH2:15][NH:16][CH:17]=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.CO>[C:7]1([S:13]([CH:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[CH2:15][NH:16][CH:17]=[O:18])=[O:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc2ccccc2c1C(CNC=O)Sc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2ccccc2c1C(CNC=O)S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A concentrated solution of sodium metaperiodate (2139 mg. 10 mmol) in water is added dropwise at 0° C. under cooling to a solution of 1-(1-phenylthio-2-formylaminoethyl)-2-methoxy-naphthalene (3374 mg, 10 mmol) in methanol (100 ml). The reaction is then stirred at room temperature for 24 h. The solids are filtered off and washed several times with ethyl acetate (1000 ml). The filtrate and washings are combined and then evaporated under vacuum to yield crude title compound in about 100% yield (3534 mg ) which is used in the next step without further purification.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:26])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Nc1cccc(S(=O)(=O)NC(=O)c2ccccc2)c1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(S(=O)(=O)NC(=O)c3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) was reacted with 3-amino-N-benzoyl-benzenesulfonamide using essentially the same procedure as in Example 20, step d. The crude product was purified by flash column chromatography (silica, ethyl acetate/hexane 2:1) to afford the title compound. 1H NMR 300 MHz, d6-DMSO) 12.52 (1H, br s), 9.85 (1H, br s), 8.55 (1H, br s), 7.89 (3H, m), 7.62-7.29 (9H, m), 2.99 (2H, m), 2.54 (3H, s), 1.95 (3H, s), 1.66-1.40 (14H, m). Found: C, 67.51; H, 6.33; N, 8.63%; C36H38N4O4S.1.0 H2O requires: C, 67.48; H, 6.29; N, 8.74%.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C1(=O)O[CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:16][CH2:15][OH:14])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: O=C1OCCO1
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCCO)cc1
Temperature: 0 °C

Procedure:
4-(1-Methylpropoxy)phenol (6.92 g, 41.6 mmol), ethylene carbonate (7.34 g, 83.2 mmol) and dimethylformamide (DMF; 45 ml) are mixed under N2. With stirring, the mixture is degassed (3X) by alternate application of vacuum and N2. Potassium carbonate (11.51 g, 83.2 mmol) is then added, under N2, and the mixture is heated at 90° for 27 hours. The reaction mixture is then poured into ice water and 10 ml of 40% potassium carbonate solution is added to increase the pH to 13. The aqueous phase is extracted with ether (3X) and the organic layers are washed with 40% KOH, with water until neutral and with brine, dried, filtered and the solvent evaporated to give 2-[4-(1-methylpropoxy)phenoxy]ethanol.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].C([Sn](CCCC)(CCCC)[C:34]([O:36][CH2:37][CH3:38])=[CH2:35])CCC>O1CCOCC1.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>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:9]1[C:8]([NH:7][C:5]2[S:6][C:2]([C:34]([O:36][CH2:37][CH3:38])=[CH2:35])=[C:3]([C:25]([F:28])([F:27])[F:26])[N:4]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1sc(Nc2cccnc2Oc2ccccc2C(C)(C)C)nc1C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a, 1.3 g, 2.75 mmol) in dioxane (30 mL) was added tributyl(1-ethoxyvinyl)tin (1.1 mL, 3.3 mmol) was degassed and Pd(PPh3)4 (160 mg, 0.14 mmol) was added. The mixture was degassed and heated at 100° C. overnight. The mixture was concentrated on vacuum, dissolved in EtOAc and treated with saturated KF solution. The solid was removed by filtering through a pad of Celite®. The filtrate was extracted with EtOAc. The organic layers were combined, washed with bring, dried over magnesium sulfate and concentrated to give crude Example A154a (1.12 g) as a brown oil.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.CS([Cl:16])(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH3:11][N:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:3]1[CH2:2][Cl:16]
Reactant: Cn1c(CO)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(CCl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A stirred solution of the above alcohol (43) (0.13 g, 0.83 mmol) in dry CH2Cl2 (5 mL) at 0° C. was treated with methanesulfonyl chloride (0.36 mL. 1.25 mmol), followed by Et3N (0.50 mL). After stirring at 0° C. for 15 min, the mixture was evaporated to dryness under reduced pressure at room temperature, and the resulting brown solid was partitioned between water and EtOAc. Workup of the organic layer gave a crude product which was was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (1:1) gave 1-methyl-2-chloromethyl-5-nitropyrrole (44) (0.13 g, 88%), mp (EtOAc/petroleum ether) 82.5-83.5° C. 1H NMR (CDCl3) δ 7.16 (d, J=4.4 Hz, 1 H, H-4), 6.26 (d, J=4.4 Hz, 1 H, H-3), 4.60 (s, 2 H, CH2Cl), 4.02 (s, 3 H, CH3). Anal. Calculated for C6H7ClN2O2 : C, 41.3; H, 4.0; N, 16.0. Found: C, 41.4; H, 4.0; N, 15.9%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)(C)(C)C.[OH:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][C:21]([CH:22]=O)=[C:20]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH:19]=1.[CH2:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1.[O-]S(C(F)(F)F)(=O)=O.[In+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][CH:22]([C:21]1[C:20]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:19][C:18]([OH:17])=[C:25]([O:26][CH3:27])[CH:24]=1)[CH:38]1[CH2:39][C:40]3[C:45]([CH:37]21)=[CH:44][CH:43]=[CH:42][CH:41]=3
Reactant: COc1cc(C=O)c(Oc2ccccc2OC)cc1O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: C1=Cc2ccccc2C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: CC#N
Product: COc1cc(C2Nc3ccc(CN)cc3C3c4ccccc4CC23)c(Oc2ccccc2OC)cc1O
Temperature: 70 °C

Procedure:
(4-Amino-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.9 mmole) was dissolved in acetonitrile (5 mL). The solution was treated with 4-Hydroxy-5-methoxy-2-(2-methoxy-phenoxy)-benzaldehyde (250 mg, 0.9 mmole) and indene (130 mg, 1.1 mmole). Indium triflate (600 mg, 1.1 mmole) was added and the reaction was heated at 70° C. for 18 hours to give 4-(2-Aminomethyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-2-methoxy-5-(2-methoxy-phenoxy)-phenol which was then purified using reverse phase HPLC.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=2[CH2:18]O)[CH:5]=[CH:6][CH:7]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:9](=[O:20])[C:10]3[C:11](=[CH:12][CH:13]=[C:14]([C:16]#[N:17])[CH:15]=3)[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(C#N)ccc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1N1Cc2ccc(C#N)cc2C1=O
Temperature: 25 °C
Yield: 62.1 %

Procedure:
Step 2 A solution of N-(3-bromo-2-methylphenyl)-5-cyano-2-(hydroxymethyl)benzamide (170 mg, 0.492 mmol) in THF (20 mL) was treated with di-tert-butyl azodicarboxylate (113 mg, 0.492 mmol) and tributylphosphine (0.119 mL, 0.492 mmol) and stirred at rt. After 2 h the mixture was concentrated and the residue was column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-3-oxoisoindoline-5-carbonitrile (100 mg, 62%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.07 (1 H, d, J=8.1 Hz), 7.82-7.89 (2 H, m), 7.64 (1 H, dd, J=7.8, 1.4 Hz), 7.13-7.25 (2 H, m), 4.78 (2 H, s), 2.30 (3 H, s). Mass spectrum m/z 327, 329 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#N.[OH-:16].[K+].C(O)C[OH:20]>O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([OH:20])=[O:16]
Reactant: OCCO
Reactant: [OH-]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: [K+]
Solvent: O
Product: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Yield: 86.3 %

Procedure:
A mixture of 11.27 g. (0.046 mole) of 4-cyano-4-phenylcyclohexanone, ethylene ketal (prepared in Example 18) and 11.3 g. of potassium hydroxide in 90 ml. of ethylene glycol is heated at reflux for about 16 hours. The resulting solution is allowed to cool, diluted with water and washed with ether. The aqueous layer was covered with ether and then cautiously acidified. The aqueous layer is extracted with two additional portions of ether and the extracts combined. The extracts are evaporated to dryness and the solid remaining is recrystallized from a mixture of ethylene chloride and Skellysolve B to give 10.51 g. (86.3% yield) of 4-carboxy-4-phenylcyclohexanone, ethylene ketal, having a melting point of 136° to 140°C.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:19])[CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(C(C)=O)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2c(C(C)=O)cccc2c1Cl

Procedure:
A solution of 3-butyryl-8-acetyl-4(1H)-quinolone (8.4 g) in phosphoryl chloride (30 ml) was heated at reflux for 1 hour, then poured onto ice and the product extracted into ether. Drying and evaporation gave crude 3-butyryl-4-chloro-8-acetylquinoline as a dark solid, which was used without further purification.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[O:18]1[CH2:20][CH:19]1[CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CC(O)C.O>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][CH2:21][CH:19]([OH:18])[CH2:20][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:24][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CCC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Solvent: O
Solvent: CC(C)O
Product: CCC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
tert-Pentyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.0 g; 4.16 mmol; from step (b) above) was dissolved in IPA:H2O (9:1; 4 mL) and 4-(2-oxiranylmethoxy)benzonitrile (1.46 g; 8.32 mmol; see Example A above) was added to the resultant solution. The reaction mixture was stirred at 60° C. for 3 h, concentrated and the residue subjected to column chromatography (DCM:MeOH; gradient 1:0 to 68:32) giving the title compound (1.45 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11]2)=[CH:6][C:5]=1[NH2:21])([O-:3])=[O:2].CC1(C)[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=O)[O:24]1>>[C:32]([C:31]1[CH:30]=[C:29]([C:27](=[O:28])[CH2:26][C:25]([NH:21][C:5]2[CH:6]=[C:7]([N:10]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:11]3)[CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:24])[CH:36]=[CH:35][CH:34]=1)#[N:33]
Reactant: Nc1cc(-n2ccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-nitro-5-(3-phenyl-pyrrol-1-yl)-phenylamine (Example F6) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange solid (267 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]2[C:9]=1[NH:8][C:7](=[S:10])[NH:6]2.[CH2:15](I)[CH3:16].[OH-].[Na+]>CO>[CH2:15]([S:10][C:7]1[NH:8][C:9]2[C:5](=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:3][C:2]=2[CH3:1])[N:6]=1)[CH3:16]
Reactant: COC(=O)c1sc(C)c2[nH]c(=S)[nH]c12
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2,3-dihydro-4-methyl-2-thioxothieno[3,4-d]imidazole-6-carboxylate (1.1 g), ethyl iodide (0.75 g), 2N NaOH (2.4 ml) and methanol (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and there was added water to give crystals. Recrystallization from ethyl acetate--hexane afforded colorless prisms (1.0 g, 83%), m.p. 159°-160° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=CC=[CH:3][CH:2]=1.[BrH:8].O1[CH2:14][CH2:13][CH2:12]OO1>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(O)(=O)C>[Br:8][CH2:12][C:13]1[CH:14]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1
Reactant: Br
Reactant: C1COOOC1
Reactant: Cc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Solvent: CC(=O)O
Product: Cc1ccc(CBr)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Toluene (18 g) was added to a mixture of acetic acid (25 ml) and hydrobromic acid (95 ml), followed by trioxane (6.6 g) and benzyltriethylammonium bromide (2.0 g). The mixture was then heated to 70° C. and stirred well at the same temperature for 20 hours. After cooling to room temperature, the mixture was extracted with dichloromethane and then concentrated to give oil residue. The oil residue was distilled under vacuum to give the target product, 4-bromomethyltoluene (30.0 g). Result of measurement by NMR(CDCl3, ppm) was 2.4(3H, s), 4.5(2H, s), 7.3(4H, dd).