Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.BrC1C=CC(C(=[O:20])C)=CC=1.[OH-].[Cs+]>>[OH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cs+]
Agent: [OH-]
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following general operating mode A, 4′-iodoacetophenone or 4′-bromo acetophenone (246 mg or 199 mg, 1.0 mmol) were reacted with cesium hydroxide at respectively 110 or 130° C. to afford the expected product in the form of a white solid at respective yields of 90% and 84% (eluant: ethyl acetate/heptane 20:80).
Reaction SMILES: [CH3:1][CH:2]([NH:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][C:26](=[O:29])[N:25]3[CH2:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:33]=[C:24]23)[CH:20]=[CH:19][N:18]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([N+:13]([O-])=O)[CH3:12])=[CH:6][CH:5]=1>[Pd].CO>[NH2:13][CH:11]([CH3:12])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH:2]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[N:25]4[CH2:30][CH:31]=[C:32]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:33]=[C:24]34)[CH:20]=[CH:19][N:18]=2)[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=Cc1ccc(CC(C)Nc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(N)Cc1ccc(CC(C)Nc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1

Procedure:
Through a mixture of 1-(2-{1-methyl-2-[4-(2-nitro-propenyl)-phenyl]-ethylamino}-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (10 mg, 0.02 mmol) and palladium on carbon (cat) in methanol was bubbled hydrogen through a balloon for 17 h. The mixure was filtered through celite, concentrated and chromatographed on silica gel using 0-4% MeOH/CH2Cl2 to afford an off-white solid. M+1=496. 1NMR (CDCl3) d (3H, 1.28 ppm), d (3H, 1.79 ppm), m (1H, 1.86 ppm), m (2H, 2.22 ppm), m (1H, 2.80 ppm), m (1H, 2.94 ppm), m (3H, 3.75 ppm), m (4H, 4.15 ppm), m (1H, 4.30 ppm), s (1H, 6.60 ppm), d (3H, 7.15 ppm), d (2H, 7.22 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.17 ppm).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.I[CH2:15][CH2:16][OH:17].[C:18]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([OH:35])[C:29]([CH3:37])([CH3:36])[CH2:28]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCCC>ClC1C=CC=CC=1.CCCCCCC.C(OCC)(=O)C>[C:18]([O:26][CH:27]1[CH2:28][C:29]([CH3:37])([CH3:36])[N:30]([O:35][CH2:15][CH2:16][OH:17])[C:31]([CH3:33])([CH3:34])[CH2:32]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCI
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCCO

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-iodoethanol and 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine in chlorobenzene. The crude reaction mixture is passed through silica gel with heptane and then heptane/ethyl acetate to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15](=[O:17])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)N1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)CCC1NC(=O)OCc1ccccc1

Procedure:
WO 93/09120 describes a process for the preparation of dimiracetam (2,5-dioxohexa-hydro-1H-pyrrolo[1,2-a]imidazole) 1 and related compounds. 5-Ethoxy-2-pyrrolidone is reacted with benzyl carbamate with a catalytic amount of p-toluenesulfonic acid to give 5-benzyloxycarbonylamino-2-pyrrolidone. This compound is then deprotonated at the pyrrolidine nitrogen with sodium hydride in acetonitrile, and reacted with ethyl bromoacetate to give ethyl 5-benzyloxycarbonylamino-2-oxo-1-pyrrolidine-acetate 2. Cyclization can then be performed after cleavage of the ethyl ester and/or the benzyloxycarbonyl protecting group in the presence of a variety of cyclizing agents.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH2:25][OH:26])[CH:20]([NH:27][C:28](=[O:57])[C:29]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)=[N:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:19]2=[O:58])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1.ClCCl.O=[Mn]=O.[O-2].[O-2].[Mn+4]>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[O:26])[CH:20]([NH:27][C:28](=[O:57])[C:29]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)=[N:30][O:31][C:32]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:19]2=[O:58])=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CO)CSC23)ns1
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=O)CSC23)ns1
Yield: 52.1 %

Procedure:
2.2 (via MnO2): To a solution of 10.00 g (12.36 mMol) 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester in 100 ml tetrahydofurane and 100 ml dichloromethane is added in 13 portions in 15 min intervals 65 g manganese dioxide (0.75 Mol) with stirring. To the resulting suspension is added 10.0 g active coal and 500 ml ethyl acetate. The mixture is concentrated to a volume of 200 ml. To resulting suspension is added 100 ml n hexane and the mixture is purified by chromatography over 500 g silica gel using 1:2 mixture of n hexane: ethyl acetate as eluent. The product fraction are collected and evaporated to dryness under aspirator vacuum. The resulting foam is triturated with 30 ml t-butylmethyl ether to give 5.2 g of the title compound as a yellowish powder with identical analytical characteristics as in example 2.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=[O:23].[Na+].OS([O-])=O.[Na+]>Cl.O>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Clc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1.17 g (122) in 17 mL concentrated HCl: 0.35 g NaNO2 in 5 mL water were added slowly dropwise, so that the temperature remained below 5° C. The solution was agitated for 2 hours at 60° C., neutralized with NaHSO3 and extracted with ether (4×50 mL). The combined organic phases were dried with Na2SO4, evaporated and distilled in a bulb tube (Kp: 0.05 mbar; 140° C.): 0.1 g (123) (123) as colorless oil. DC: CHCl3/methanol (9:1).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([CH3:14])[O:11][CH2:12][CH3:13].C(O)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:14])([CH3:9])[O:11][CH2:12][CH3:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](C)C
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCO[Si](C)(C)CCc1ccccc1
Temperature: 41 °C
Yield: 74.5 %

Procedure:
312 mg Of styrene and 312 mg of dimethylethoxysilane were placed in a glass reaction tube and 0.006 ml of acetic acid was added. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 41° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 80% and phenethyldimethylethoxysilane was produced at a yield of 74.5%. The yield of (α-methylbenzyl) dimethylethoxysilane was 5.5%
Reaction SMILES: [Al](C)(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].C([O:16][C:17](=O)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=1[CH3:36])C.Cl>C(OCC)(=O)C.O>[CH2:30]([N:21]1[C:22]2[C:27](=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:19]([CH2:18][C:17]([NH2:13])=[O:16])=[C:20]1[CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: [NH4+]
Reactant: CCCCCCn1c(C)c(CC(=O)OCC)c2cc(OC)ccc21
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
A 2M solution of Al(CH3)3/toluene (15 mL, 0.03 mol) was added to 1.61 g (0.03 mol) of ammonium chloride while slowly keeping the temperature at 5-7° C. with an ice-water bath. The bath was removed, the mixture stirred for 0.5 hour and 1.01 g (3.05 mmol) of 1-hexyl-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was added. After stirring for 16 hours, 10 mL of water was added cautiously and the mixture added to 1N HCl and a large volume of ethyl acetate. The organic layer was separated, washed with water, sodium bicarbonate solution and dried (Na2SO4). After removing the solvent at reduced pressure the residue was crystallized from MeOH/water to give 0.37 g (40% yield) of 1-hexyl-5-methoxy-2-methyl-1H-indole-3-acetamide, mp, 120-121° C.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:8]([F:30])=[C:9]([CH:14]([O:27][CH2:28][CH3:29])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[O:16])[C:10]([F:13])=[CH:11][CH:12]=1.C(Cl)(=O)C>>[C:1]([NH:5][CH2:6][C:7]1[C:8]([F:30])=[C:9]([CH:14]([O:27][CH2:28][CH3:29])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[O:16])[C:10]([F:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CN)c1F
Reactant: CC(=O)O
Solvent: CC(=O)Cl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CNC(C)=O)c1F

Procedure:
In analogy to example 87.2 (RS)-2-(3-aminomethyl-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide acetic acid was reacted with acetyl chloride to give (RS)-2-[3-(acetylamino-methyl)-2,6-difluoro-phenyl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide. White foam. MS 402.5 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(CN2Cc3c(Oc4ccc(NS(=O)(=O)c5ccccc5F)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (45 mg, 0.11 mmol) and 2-fluorobenzenesulfonyl chloride (24 mg, 0.12 mmol) were suspended in pyridine (1 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=553, obsd.=553).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[O:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a solution of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate (360.0 g, 1.21 mol) in EtOH (6.7 L) was added wet Pd/C (55.0 g) under N2 that then was replaced by H2. The reaction mixture was stirred at rt for 4 h, filtered and concentrated to give a crude product. The crude product was slurried with EtOH (200 mL) for 2 h and then filtered. The filtered cake was washed with MTBE and the combined organic phases were concentrated to give the title compound (222.0 g, 1.07 mol, 88.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:29][CH2:30][OH:31])[C:12]=2[CH:11]=1.[H][H]>[Pd]>[OH:28][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:29][CH2:30][OH:31])[C:12]3[CH:11]=[C:10]([C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=4[O:8][CH3:9])[C:22]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=4[C:20]=3[C:19]=2[CH:18]=1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCO
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccccc1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCO
Yield: 77 %

Procedure:
Reaction of 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar-2-chloro-6-methoxyphenyl, R10═CH2CH,OH) (112) prepared as described in example 64 with hydrogen gas, using a Pd/C catalyst, according to the procedure for example 60 gave 9-Hydroxy-6-(2-hydroxyethyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-methoxyphenyl, R10═CH2CH2OH) (113) in a 77% yield as a yellow solid; mp 285–289° C. 1H NMR δ [(CD3)2SO] 10.91 (br s, 1H), 9.29 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (m, 1H), 7.33 (dd, J=8.8, 2.4 Hz, 1H), 7.12–7.02 (m, 3H), 4.84 (t, J=5.5 Hz, 1H), 4.73 (t, J=5.3 Hz, 2H), 3.76 (dt, J=5.5, 5.3 Hz, 2H), 3.68 (s, 3H). Found: C, 67.30; H, 4.47; N, 6.79. C23H18N2O5.1/2H2O requires C, 67.15; H, 4.65; N, 6.81.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=3)=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:48][CH2:49][CH:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH:69][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12](=[O:21])[C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:65][N:64]=3)=[CH:60][CH:61]=2)(=[O:54])=[O:55])[CH2:51][CH2:52]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 17 (Example 25) (0.134 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were used as-is for deprotection step. White solids (0.075 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12](=[O:34])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][C:14]=3[O:32][CH3:33])[C:4]=2[N:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12](=[O:34])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][C:14]=3[O:32][CH3:33])[C:4]=2[N:3]=1)(=[O:37])[CH3:36]
Reactant: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(N)nc12
Reactant: CC(=O)OC(C)=O
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(NC(C)=O)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-(2-amino-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (90 mg) and acetic anhydride (1.0 ml) was stirred for 1 hour at room temperature and allowed to stand overnight at the same temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The resulting solution was washed with saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-ethyl acetate=10-1) to give N-(2-acetamido-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (42 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CC(=O)O)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of m-tolylacetic acid (25.00 g, 166.5 mmol) in anhydrous carbon tetrachloride (200 ml) was added N-bromosuccinimide (30.00 g, 168.6 mmol), and the mixture was gradually heated to the boiling point. After heating the mixture under reflux for 5.5 hr, the reaction mixture was cooled to room temperature, the insoluble material was removed by filtration and washed twice with carbon tetrachloride (100 ml). The filtrate was concentrated, carbon tetrachloride (60 ml) was added and the residue was dissolved by heating at about 70° C. The solution was cooled to about 40° C., and hexane (300 ml) was added dropwise. After stirring at room temperature for 30 min, the precipitated crystals were filtered, washed with hexane and dried under reduced pressure to give (3-bromomethylphenyl)acetic acid (22.80 g, 99.53 mmol, yield 59.8%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14])=[CH:4][C:3]=1[I:24].N1C=CC=CC=1.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:12]([CH:15]([CH3:16])[CH3:17])[CH2:13][O:14][C:32]([O:34][CH3:35])=[O:33])=[CH:4][C:3]=1[I:24]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn([C@H](COC(=O)OC)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 16 (13.4 g, 29.9 mmol) and pyridine (9.7 mL, 120 mmol) in anhydrous chloroform (60 mL) at 0° C. was added dropwise a solution of methyl chloroformate (9.2 mL, 120 mmol) in chloroform (30 mL). The mixture was stirred 1 h at 0° C., and then was washed with 2 N HCl (2×60 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil (mixture of 16 and 17) was treated with pyridine (5 mL, 62 mmol) and methyl chloroformate (4.6 mL, 60 mmol) under the same conditions above another four times to achieve approximately 90% conversion. The crude product, a yellow oil, was purified on an AnaLogix chromatography system with 33-50% EtOAc/heptanes to give 7.6 g (50%, greater than 98% purity) of 17 as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: BrBr
Product: O=C1c2cc(Br)ccc2OCCC1Br

Procedure:
Following the procedure for 449, Step 1, 7-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one was reacted with bromine to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[C:28]([CH3:40])([CH3:39])[CH2:27]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]([F:15])([F:14])[F:16])=[CH:11][C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[C:9]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28]([CH3:40])([CH3:39])[CH2:27]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2Cc2ccccc2)CC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(C(=O)c2c(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2Cc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(1-benzyl-3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carbonyl)-2,2-dimethylpiperazine-1-carboxylate (103 mg, 0.178 mmol) in DCM (2 mL) was added TFA (0.234 mL, 3.03 mmol). The reaction mixture was stirred for 1 h and then cooled to 0° C. Saturated aqueous NaHCO3 (15 mL) was added. The aqueous layer was separated and extracted twice with DCM (10 mL). The combined organic phases were washed with brine (20 mL) and dried over Na2SO4. Concentration in vacuo was followed by flash chromatography (silica, gradient heptane/EtOAc, 1:0→0:1). Appropriate fractions were combined, solvents removed in vacuo and the product was placed with MeOH (5 mL) in a vial. The remaining oil was dried in vacuo at 40° C. over 6 h. SC-82 (58 mg, 67%) was obtained as a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:31])[N:20](CC2C=CC(OC)=CC=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.BrC1C=C2C(C=CNC2=O)=CC=1OC1CCNCC1>>[C:25]1([C:24]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][NH:20][C:21]3=[O:31])=[CH:16][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cc3c2=O)cc1
Agent: O=c1[nH]ccc2cc(OC3CCNCC3)c(Br)cc12
Product: O=c1[nH]ccc2cc(OC3CCNCC3)c(-c3ccccc3)cc12

Procedure:
4-[2-(4-Methoxy-benzyl)-1-oxo-7-phenyl-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (316) was deprotected following the method described for 7-bromo-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (17). Similar work up delivers the title compound as HCl-salt. Rt=1.05 min (Method B). Detected mass: 321.1 (M+H+).