Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=3)[N:10]=[C:9]([OH:22])[CH:8]=2)[S:5][CH:6]=1.[CH3:23][O:24][C:25]([C@@:27]12[CH2:45][C@H:44]1[CH:43]=[CH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:46])[C:36](=[O:47])[N:35]1[C@@H:30]([CH2:31][C@H:32](O)[CH2:33][CH2:34]1)[C:29](=[O:49])[NH:28]2)=[O:26].COC([C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1[C@@H](C[C@H](OC3C4C(=C(C)C(OC)=CC=4)N=C(C4SC=C(C#C)N=4)C=3)CC1)C(=O)N2)=O>>[CH3:23][O:24][C:25]([C@@:27]12[CH2:45][C@H:44]1[CH:43]=[CH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:46])[C:36](=[O:47])[N:35]1[C@@H:30]([CH2:31][C@@H:32]([O:22][C:9]3[CH:8]=[C:7]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)[N:12]=[C:11]([C:13]4[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=4)[N:10]=3)[CH2:33][CH2:34]1)[C:29](=[O:49])[NH:28]2)=[O:26]
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@@H](O)C[C@H]1C(=O)N2
Reactant: Cc1csc(-c2cc(O)nc(-c3nc(C(F)(F)F)cs3)n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)N1CC[C@@H](O)C[C@H]1C(=O)N2
Product: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@H](Oc3cc(-c4nc(C)cs4)nc(-c4nc(C(F)(F)F)cs4)n3)C[C@H]1C(=O)N2
Yield: 97 %

Procedure:
(1S,4R,6S,18S)-18[6-(4-Methylthiazol-2-yl)-2-(4-trifluoromethylthiazol-2-yl)-pyrimidin-4-yloxy]-13-N-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.4.0.0*4,6*]nonadec-7-ene-4-carboxylic acid methyl ester 41b was synthesized from compounds B1 (150 mg, 1.2 eq.) and 36 (44.3 mg, 1 eq), according to the procedure as described for compound 37, as a beige solid in 97% yield. MS (ESI, EI−) m/z=704 (MH−).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:3].C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:3][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:1]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-(1-methylethyl)-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.161 g, 0.670 mmol, Example 184) and triethylamine (0.290 mL, 2.083 mmol) in dichloromethane (5.82 mL) was added a solution of 2-thiophenesulfonyl chloride (0.138 g, 0.756 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (1 mL) drop-wise at room temperature. The solution was stirred for 30 min and then the mixture was concentrated. The residue was re-dissolved in CH2Cl2 and washed with water followed by brine. The organic layer was dried (Na2SO4), filtered, and concentrated to give 3-(1-methylethyl)-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-2-piperazinone (242 mg).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.11 g (0.73 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.21 g (68%) as a white solid; mp=121-123° C.; MS (+) ESI m/z=414 (M+H)+.
Reaction SMILES: [H-].[Na+].CCCCCC.[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:41])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CS(O[CH2:47][CH2:48][O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])(=O)=O>CS(C)=O.O>[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([O:41][CH2:47][CH2:48][O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:20][O:21][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCO[C@@H](CCO[Si](C)(C)C(C)(C)C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 0 %

Procedure:
Sodium hydride (2.11 g, 52.7 mmol, 60% in oil) was loaded under argon circumstance in three-necked flask and hexane (30 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (10 ml) was added and the solution was stirred at 60° C. for 1 hour. After cooling to room temperature, (S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-butanol (20.36 g, 44.0 mol) in DMSO (12 ml) was gradually dropped at room temperature to the solution and then the solution was stirred for 30 minutes. To the solution was gradually dropped 2-tert-butyldimethylsilyloxyethyl methanesulfonate (12.28 g, 48.3 mol) in DMSO (12 ml) at room temperature and then the solution was stirred for 12 hours. To the reaction mixture was added water (40 ml) and the solution was extracted with ethyl acetate. The extract was washed with water (50 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-tert-butyldimethylsilyloxy-2-(2-tert-butyldimethylsilyloxyethoxy)-1-trityloxybutane (11.2 g, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Cc1cccc(N)n1
Product: COC(=O)C(=CNc1cccc(C)n1)C(=O)c1ccc(C)c(C)c1
Yield: 171.8 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (2.01 mmol) of the crude 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester and 0.22 g (2.01 mmol) of 2-amino-6-picoline to yield 1.12 g of 2-(3,4-Dimethyl-benzoyl)-3-(6-methyl-pyridin-2-ylamino)-acrylic acid methyl ester as brown crystalline solid.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>C(Cl)Cl>[CH3:2][O:3][CH2:4][CH2:5][NH:6][CH:7]([CH3:16])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: COCCNC(C)C(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COCCNC(C)C(O)c1ccccc1

Procedure:
2-[(2-Methoxyethyl)amino]-1-phenyl-1-propanone hydrochloride as prepared in Preparation 5 is converted to the free base by mixing it with methylene chloride and a dilute basic aqueous solution, e.g., sodium hydroxide, separating the organic layer and evaporating the solvent. The residue, the free base is then reduced with sodium borohydride in ethanol to give the title compound which is then isolated by conventional means.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#N.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:27]>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C#N)c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C=O)c1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 119.8 grams (0.56 mole) of 2-methyl-2-(4-trifluoromethylphenyl)propanenitrile in 100 mL of toluene was cooled to -50° C., and 487 mL (0.73 mole) of diisobutylaluminium hydride (1.5M in toluene) was added dropwise during a 45 minute period while keeping the reaction mixture temperature between -45° and -50° C. Upon completion of addition, the reaction mixture was stirred at -50° C. for 30 minutes. The reaction mixture was then warmed to about 0° C., where it stirred for an additional 30 minutes. After this time, the reaction mixture was carefully poured into 1000 mL of ice-cold aqueous 1.5M sulfuric acid. The resultant mixture was stirred for about three hours, then it was allowed to stand for about 18 hours. The aqueous layer was separated and extracted with 200 mL of diethyl ether. The organic layer and the diethyl ether extract were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 102.3 grams of 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[C:9]2[N:45]=[C:43]([NH:42][C:32]3[CH:33]=[CH:34][C:35]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:30]([O:29][CH3:28])[CH:31]=3)[N:44]=[CH:3][C:4]=2[CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C=C1CCCC(c2ccc(Cl)cc2Cl)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(Cl)cc2Cl)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(2,4-dichloro-phenyl)-cyclohexanone (105 mg, 0.35 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (131 mg, 0.35 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (19 mg, 11%). MS ISP (m/e): 480.1 [(M+H)+]. mp 256-258° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:41]3[C:42]([CH3:56])=[C:43]([NH:48][C:49](=[O:55])[CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:44]([CH3:47])=[C:45]([CH3:46])[C:40]=3[O:39][CH2:38]2)=[CH:33][C:32]=1[O:57][CH3:58])(=O)[CH3:29].O>C1(C)C=CC=CC=1>[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:41]3[C:42]([CH3:56])=[C:43]([NH:48][C:49](=[O:55])[CH2:50][C:51]([CH3:53])([CH3:54])[CH3:52])[C:44]([CH3:47])=[C:45]([CH3:46])[C:40]=3[O:39][CH2:38]2)=[CH:33][C:32]=1[O:57][CH3:58])([CH3:29])=[CH2:1]
Reactant: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of potassium tert-butoxide (818 mg, 7.29 mmol) in toluene (45 mL) was added methyl triphenylphosphonium iodide (2.94 g, 7.29 mmol) and the resulting mixture was stirred at 120° C. for 1 hour under an argon atmosphere. To the reaction solution was added N-(3-(4-acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (2.32 g, 5.48 mmol) obtained in Example 183 and the resulting mixture was stirred at 120° C. for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.93 g (yield: 84%) of the title compound. Melting point: 186-187° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH:2]([CH3:25])[CH2:3][C:4]1[N:8]2[C:9]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.B>O1CCCC1>[NH2:1][CH:2]([CH3:25])[CH2:3][C:4]1[N:8]2[C:9]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=3[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:12][CH2:13][C:7]2=[N:6][N:5]=1
Reactant: CC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: B
Solvent: C1CCOC1
Product: CC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)NC2

Procedure:
In the manner given in Example 23 a mixture of 1-(2-aminopropyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine and tetrahydrofuran was treated with borane to give 1-(2-aminopropyl)-8-chloro-5,6-dihydro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:41]4[CH:40]=[CH:39][C:38](C=O)=[CH:37][C:36]=4[S:35][C:34]4[C:29]3=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:13]3[C:18]([S:19][C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[S:35][C:36]4[C:41]3=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:19][C:20]=2[CH:21]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1N2CCCCCCN1c2ccccc2Sc2cc(C=O)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: c1ccc2c(c1)Sc1ccccc1N2CCCCCCN1c2ccccc2Sc2ccccc21

Procedure:
Phosphorus oxychloride was added dropwise to dry dimethylformamide (1:1.2 molar ratio) at 0° C. under nitrogen. A solution of 1,6-di(10H-10-phenothiazinyl)hexane (obtained in the previous step) in dry DMF was added stepwise to the reaction flask. The reaction mixture was stirred at 70° C. until the starting compound reacted completely as indicated by TLC. The reaction mixture was cooled to room temperature, poured into ice water, and neutralized with a dilute KOH solution until the pH reached 7-8. The aqueous solution was extracted several times with chloroform. The combined chloroform solutions were washed with water, dried with anhydrous sodium sulfate, and filtered. The solvent was removed by distillation. The crude product was purified by column chromatography using a mixture of ethyl acetate and hexane in a volume ratio of 1:8 as the eluent. The yield of 10-[6-(3-formyl-10H-10-phenothiazinyl)hexyl]-10H-3-phenothiazine carbaldehyde was 56%. The 1H-NMR spectrum of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 1.35-1.50 (m, 4H), 1.55-1.90 (m, 4H), 3.82 (t, 4H), 6.73-7.19 (m, 14H), and 9.80 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]([C:12]([OH:14])=O)=[CH:11]2.[Si:24]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][C:10]([C:12](=[O:14])[N:35]([CH2:34][CH2:33][CH2:32][O:31][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:36][CH2:37][CH3:38])=[CH:11]2
Reactant: CCCNCCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(Br)ccc2C=C(C(=O)O)C1
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI (+) m/z 594, 596 (M+1, Br pattern) detected.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O:17]=[C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:19]=[CH2:20].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:20][CH2:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)N1CCOCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC(=O)N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following the procedure of Example 4, 2,6-bis-(1,1-dimethylethyl)4-mercaptophenol (2.389, 0.01 mole) and (1-oxo-2-propenyl)morpholine (1.41 g, 0.01 mole) in methanol (75 ml) were combined with triethylamine (1.5 ml) and stirred for 12 hours at room temperature. The solvent was evaporated under a nitrogen stream leaving an orange oil which was chromatographed over silica. The product was recrystallized from a mixture of hexane, ethyl ether and methanol and the resulting white solid dried to yield the title compound, m.p. about 136.5°-137.5° C.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](Cl)=[O:30]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:29]([C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)=[O:30])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc5ccccc5c4)CC3)cccc2n1
Yield: 77 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-Naphthoyl chloride (78.2 mg; 0.41 mmol) to obtain 61.6 mg. (77% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.59 (s, 1H), 8.02 (m, 8H), 7.6 (m, 5H), 7.5 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.67 (br s, 2H), 4.64 (br s, 1H), 3.76 (br s, 1H), 3.42 (m, 4H), 2.85 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46].[ClH:47]>>[ClH:28].[ClH:47].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:19][CH2:18]2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: CCN(CC)C1CCC(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Agent: Cl
Product: CCN(CC)C1CCC(Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 50 %

Procedure:
Following general procedure D, N1-[6-bromo-3-(methylsulfonyl)quinolin-4-yl]-N4,N4-diethylcyclohexane-1,4-diamine (40 mg, 0.088 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.176 mmol) to afford, after treatment with 1M HCl, the desired product (24.5 mg, 50%) as an orange-brown solid: 1H NMR (500 MHz, DMSO-d6+D2O) δ 8.91 (d, J=8.0 Hz, 1H), 8.44-8.32 (m, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.48-7.27 (m, 2H), 3.98-3.95 (m, 3H), 3.46 (d, J=11.4 Hz, 5H), 3.28-3.03 (m, 5H), 2.38 (s, 2H), 2.27 (d, J=13.0 Hz, 1H), 2.15 (s, 1H), 2.10-1.96 (m, 2H), 1.90-1.69 (m, 3H), 1.33-1.23 (m, 6H); ESI MS m/z 532 [C27H34ClN3O4S+H]+; HPLC 98.9% (AUC), tR=10.49 min.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO.[NH4+].[OH-]>O.CO.C(Cl)(Cl)Cl>[CH:30]1([O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:18]2[C:19]3[C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4OC4CCCC4)c3c2CC1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: OCCO
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OC2CCCC2)c1

Procedure:
The 3-benzoyl-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.73 g, 1.6 mmol), potassium hydroxide (2.07 g, 32.1 mmol), and ethylene glycol (15 mL) were heated to 170° C. for 2.67 hours. The reaction was diluted with water and extracted with ethyl acetate (233). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown oil which was passed through a column of silica gel with 3% methanol/chloroform with 1% NH4OH to give 419 mg (74%) of a white foam as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1 H), 7.35-7.26 (m, 3 H), 7.15-7.11 (m, 1 H), 7.03-6.96 (m, 2 H), 6.91 (d, J=7.2 Hz, 1 H), 4.69-4.65 (m, 1 H), 3.11-3.07 (m, 2 H), 2.99-2.95 (m, 2 H), 2.87-2.81 (m, 2 H), 2.45-2.39 (m, 2 H), 1.73-1.67 (m, 4 H), 1.48-1.45 (m, 4 H); HRMS (FAB) calcd for C23H26N2O+H1: 347.2123 found 321.2134.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH:37]3[CH2:39][CH2:38]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:37]1([C:32]2[CH:31]=[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:40])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)[CH:35]=[C:34]([CH3:36])[N:33]=2)[CH2:38][CH2:39]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M237) (273 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (177 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[Br:14]Br.O>C(O)(=O)C>[Br:14][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1[nH]c2ccc(Cl)cc2c1Br
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
To a solution of 5-chloro-1H-indole-2-carboxylic acid (2.0 g, 10.2 mmol) in acetic acid (24 mL) was added a solution of bromine (0.53 mL, 10.2 mmol) in acetic acid (16 mL). After 20 minutes, the mixture was poured into water and extracted with chloroform twice. The combined extracts were washed with water twice and brine, dried over magnesium sulfate and concentrated. The product was obtained as a solid (2.5 g, 89%).