Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OC(=O)C)C.[Pd].[Cl-].[Cl-].[Zn+2]>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: NCc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 400 ml ethylacetate, 70 g (0.27 moles) anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 3 hrs (TLC control for checking conversion to N-benzyl carvedilol). The reaction mixture is cooled to ambient temperature and quenched into 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered and the filtrate subjected to hydrogenation reaction. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 4.0 Kg/cm2 at temperature of 60-70° C. for a period of about 10 hours. The reaction mixture is filtered and filtrate concentrated to about 3-4 volumes of the original volume and left for crystallisation of crude carvedilol for a period of about 10 hrs and filtered to obtain carvedilol (50 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (42 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18]O)[C:13]2[C:20]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][CH:22]=[C:23]([Cl:24])[C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:13]=3[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(C)cc3Br)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-[2-[(2-bromo-4-methylphenyl)amino]-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol) (Reference Example 54; 1.02 g, 2.13 mmol) in pyridine (2.5 mL) was added methanesulfonyl chloride (824 μL, 10.65 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude mesylate (MS Calcd.: 555; Found: 556 (M+H)) was subjected for the next step without further purification. To the crude material in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (588.8 mg, 4.26 mmol). The reaction mixture was stirred at 80° C. for 12 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound as a colorless powder (810.1 mg, 1.77 mmol, 83% (2 steps)).
Reaction SMILES: [Na].[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[C:3]1C=CC=C[CH:4]=1.C1C[O:19]CC1>CCCCCC>[CH:4](=[O:19])[CH2:3][CH2:2][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [Na]
Solvent: CCCCCC
Product: CCCCCCCCC=O
Yield: 92 %

Procedure:
Using a Fisher-Porter bottle, 0.86 g (37.4 mmol) of solid sodium metal and 2.91 g (16 mmol) of benzophenone were added to 40 ml of dry, degassed THF under N2 flow. The reaction turned blue, characteristic of the ketyl. The Fisher-Porter bottle was then pressured up to 43 psi over atmospheric with CO and the whole reaction stirred vigorously using a magnetic stirrer at 120°. At this pressure THF can reach temperatures in excess of 100° before boiling. The reaction was cooled to 60° and 2.25 ml (16.8 mmol) of Fe(CO)5 was added. A white precipitate remained after addition of n-hexane. Washing the white precipitate and pumping to dryness gave a product that yielded 92% nonanal based on 214 MW for Na2Fe(CO)4. The product of this example was not solvated.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (50 mg, 55%), MS (ISP) m/z=363.5 [(M+H)+], mp 214° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])\[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])(/[C:9](=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:16])[CH3:19]
Reactant: C#CCCCCCCCCCCC
Reactant: CCOC(=O)/C(=C\c1ccccc1Br)P(=O)(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Reaction time: 42 h
Yield: 25.3 %

Procedure:
Ethyl 3-(2-bromophenyl)-2-E-(diethoxyphosphinyl)-propenoate (7.84 g, 20.0 mmol) prepared according to Example 4 was placed in a three neck round bottom flask equipped with a condenser, stir bar, internal thermometer, and argon inlet. 1-Tridecyne (6.30 g, 34.9 mmol) and triphenylphosphine (0.161 g, 0.614 mmol) were added along with triethylamine (110 ml) and the system was degassed by repeated vacuum-argon cycles. Under an argon atmosphere, palladium acetate (0.048, 0.214 mmol) was added, and heating in an oil bath (100°-105° C.) was started. The internal temperature stayed in the range of 89°-92° C. during the reaction. Within a few hours a light precipitate started forming. After about 42 hours, additional tridecyne (1.0 g, 5.5 mmol) was added. The reaction was stopped after 53 hours. After cooling the reaction mixture was filtered and the precipitate was washed with triethylamine. The filtrate was stripped down to a reddish oil. Multiple chromatographies on silica eluting with ethyl acetate in hexane (32% ethyl acetate was best) yielded a yellow liquid, 2.43 g, 5.08 mmol, 25.3% yield; 1H NMR (CDCl3) ∂0.88 (m, 3H), 1.17 (t, J=7.2 Hz, 3H), 1.21 to 1.48 (several m, 22H), 1.64 (quintet, J=7.5 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 4.22 (m, 4H), 7.19 to 7.48 (several m, 4H), 8.06 (d, J=23.7 Hz, 1H); CI mass spectrum m/z 491 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]1[C:18](=[O:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].[BH4-].[Na+].C(Cl)Cl>C(O)C>[CH3:3][CH:2]([CH2:4][C@H:5]1[C@H:18]([OH:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:1]
Reactant: COc1cc2c(cc1OC)[C@H]1CC(=O)[C@H](CC(C)C)CN1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@H]1C[C@@H](O)[C@H](CC(C)C)CN1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0.11 M solution of (+)-TBZ (15) in ethanol at 0° C. was added NaBH4 (2.85 eq). The reaction mixture was allowed to stir for 60 min. at room temperature. The solvent was carefully removed under reduced pressure, and the residue was taken up in dichloromethane and washed with three portions of saturated aqueous K2CO3. The aqueous washings were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to provide a colorless oil that crystallized on standing under high vacuum. Purification of the crude product was achieved by chromatography on SiO2 (2.5-5% MeOH—CH2Cl2, elution was observed at 285 nm) UV active fractions were reanalyzed by TLC. Two products, 18 and 19, were isolated from this procedure. The major product 18 was a colorless solid 74%: [α]26D +48 (c 0.30, CH2Cl2) 1H NMR (CD2Cl2) δ 0.93 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.04 (ddd, J=14.6, 8.7, 4.3 Hz, 1H), 1.42 (dd, J=20.2, 11.4 Hz, 1H), 1.59 (ddd, J=13.7, 9.6, 3.3 Hz, 1H), 1.64-1.78 (m, 2H), 1.96 (apparent t, J=11.4 Hz, 1H), 2.27 (br s, 1H), 2.40-2.48 (m, 1H), 2.54 (ddd, J=12.3, 3.7, 2.3 Hz, 1H), 2.60-2.67 (m, 1H), 2.95-3.09 (m, 3H), 3.11 (apparent d, J=11.1 Hz, 1H), 3.35 (ddd, J=10.4, 10.4, 4.5 Hz, 1H), 3.80-3.81 (m, 6H), 6.60 (s, 1H), 6.69 (s, 1H); 13C NMR (CD2Cl2) δ 21.61, 24.02, 25.33, 29.30, 39.68, 40.81, 41.58, 51.83, 55.74, 55.91, 60.02, 60.92, 74.32, 108.42, 111.73, 126.68, 129.76, 147.35, 147.61; HRMS-(ESI+) calcd for (C19H29NO3+H) ([M+H]+ 320.2226, found 320.2242. The minor product 19 was a yellow oil 4%: 1H NMR (CD2Cl2) δ 0.94 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.13-1.20 (m, 1H), 1.24-1.34 (m, 2H), 1.60-1.77 (m, 2H), 1.89-2.00 (m, 1H) 2.36-2.44 (m, 2H), 2.53 (ddd, J=10.5, 10.5, 3.8 Hz, 1H), 2.58-2.70 (m, 2H), 2.91-2.98 (m, 1H), 2.98-3.09 (m, 1H), 3.48 (apparent d, J=11.6 Hz, 1H), 3.80-3.82 (apparent s, 6H), 4.07 (apparent d, J=3.1 Hz, 1H), 6.60 (s, 1H), 6.68 (s, 1H); 13C NMR (CD2Cl2) δ 22.74, 22.81, 24.87, 29.30, 37.83, 38.87, 39.42, 52.44, 55.76, 55.96, 56.32, 56.43, 67.88, 108.45, 111.78, 127.18, 130.38, 147.30, 147.54.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].[Na]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1
Agent: [Na]
Product: CCOC(=O)C(C(=O)OCC)c1cccc(Oc2ccccc2)c1

Procedure:
The method which comprises brominating m-methyldiphenyl ether with N-bromosuccinimide to form m-(bromomethyl)diphenyl ether, reacting it with sodium cyanide in dimethylsulfoxide to form m-(cyanomethyl)diphenyl ether, hydrolyzing and esterifying it to form ethyl α-(m-phenoxyphenyl)acetate, reacting the resulting ester with diethyl carbonate in the presence of metallic sodium to form diethyl 2-(m-phenoxyphenyl)malonate, reacting the product with methyl iodide to form diethyl 2-methyl-2-(m-phenoxyphenyl)-malonate, hydrolyzing the product to form 2-methyl-2-(m-phenoxyphenyl)malonic acid, and decarboxylating the product under heat to form α-(m-phenoxyphenyl)propionic acid (Japanese Pat. No. 45586/76).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1.C(Cl)(Cl)Cl>CCCCO.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[N:10]=1
Reactant: NCc1cccnc1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Solvent: CO
Product: Fc1nc(NCc2cccnc2)c2nc[nH]c2n1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.9 g, 1 eq, 5.22 mmol) in n-BuOH (60 mL) under an argon atmosphere, cooled to −20° C., was added DIEA (2.5 mL, 2.75 eq, 14.35 mmol) followed by C-pyridin-3-yl-methylamine (0.58 mL, 1.1 eq, 5.69 mmol). The reaction mixture was stirred at −20° C. for 3 h, and then allowed to return to room temperature over 2 h, when TLC (CHCl3: MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (97:3→90:10), to afford the title compound as a white solid. Yield: 1.08 g (85%). Mp 218-220° C. 1H-NMR (d6-DMSO, 250 MHz): δ4.65 (d, 2H, J=5.37 Hz, —HNCH2-Pyr), 7.34, 8.43, 8.57 (3×m, 4H, Pyr), 8.10 (s, 1H, —N═CH—NH—), 8.83 (bs, 1H, —HNCH2-Pyr), 13.07 (bs, 1H, —N═CH—NH—). FABMS m/z (relative intensity): 245 ([M+H]+, 40), 176 (27), 154 (100), 136 (74). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected: Measured) C11H9N6F .0.2H2O: C, 53.31; 54.03; H, 3.82; 3.83; N, 33.91; 32.74.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH2:4][CH2:3]1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH:9]([O:8][CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCC(OC(c2cccc([N+](=O)[O-])c2)c2nc3ccccc3[nH]2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(OC(c2cccc(N)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of 2-[(1-methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1H-benzimidazole (110 mg) in ethanol is added tin(II)dichloride (340 mg). The reaction mixture is refluxed for 2 hours. The solution is basified by adding a solution of 10N sodium hydroxide to pH 10. The aqueous phase is extracted with chloroform. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine melting at 100° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21](OC)=[O:22])[CH2:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[BH4-].O.Cl>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([CH2:21][OH:22])[CH2:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Temperature: 0 °C
Yield: 85 %

Procedure:
Dimethyl 13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (prepared according to International patent application publication WO 2006/020082) was dissolved in anhydrous THF (0.02 M) and after cooling at 0° C. BH3THF complex (1.5 eq.) was added followed by LiBH4 (1 eq.) and water (4 eq.). The mixture was left stirring at RT for 2h, then 1N hydrochloric acid was slowly added. The crude was extracted twice with EtOAc, dried over Na2SO4, filtered, and all volatiles were removed in vacuo to obtain desired compound as a yellow solid (85%) that was used in the next step without purification. (ES+) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:18][C:7]1[NH:8][C:9]2[C:5]([N:6]=1)=[C:4]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(Br)nc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 39.8 %

Procedure:
To a solution of 2-chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (950 mg, 3.74 mmol) in CH2Cl2(19 mL) was added bromine (0.23 mL, 4.49 mmol). The mixture was stirred at ambient temperature for 19 hours. Saturated sodium thiosulfate was added. The aqueous layer was extracted with dichloromethane two times. Organic layers were combined and dried over Na2SO4 and solvent was removed under reduced pressure. The crude was purified by flash column chromatography (0-70% EtOAc/cyclohexane gradient) to furnish product as a white solid (495 mg, 39%). LC-MS at 254 nm; [M+H] 334.1; Rt 0.89 min; (LCMS method 1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].[CH3:30][O:31][CH2:32]I>CN(C)C=O>[CH3:30][O:31][CH2:32][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: COCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 23.1 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.15 g), dimethylformamide (25 ml), and iodomethyl methyl ether (0.50 g), the title compound (0.26 g) was obtained as an amorphous solid, MS, m/z: 399.2(M+H)+, 797.2 (2M+H)+.
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24]C(C)(C)O[C:27](=[O:29])[CH:28]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]4)=[C:11]([F:21])[CH:10]=3)[CH2:22][C:23](=[O:24])[CH2:28][C:27](=[O:29])[O:32]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCC1

Procedure:
The desired product was prepared analogously to Example A(86) step 5 substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile (1.00 g, 2.2 mmol) from step 3 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 0.477 g, 57%. 1H NMR (CDCl3) δ: 1.79-2.05 (br, 8H), 2.14-2.19 (m, 2H), 2.21-2.29 (m, 1H), 2.49 (p, J=9.35 Hz, 1H), 2.65-2.76 (m 1H), 2.83-2.95 (m, 4H), 3.00 (d, J=5.05 Hz, 2H), 3.02-3.10 (m, 2H), 3.66 (d, J=3.28 Hz, 2H), 7.12 (dd, J1=11.24 Hz, J2=1.64 Hz, 1H), 7.17 (dd, J1=7.96 Hz, J2=1.64 Hz, 1H), 7.38 (t, J=7.96 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:20](O)=[O:21])=[CH:4][C:3]=1[CH3:23].C(Cl)CCl.C1C=CC2N(O)N=[N:34]C=2C=1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]([C:20](=[O:21])[NH2:34])=[C:6]2[C:14]=1[C:13]1[CH:12]=[CH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=1[NH:7]2
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(C)c(Br)c12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(C)c(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid (1.40 g, 3.72 mmol), EDC (1.070 g, 5.58 mmol), and HOBT (0.855 g, 5.58 mmol) in a mixture of THF (30 mL) and DCM (5 mL) was stirred at room temperature for 60 min. Ammonium hydroxide (0.217 mL, 5.58 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. Phase separation could not be achieved, so the mixture was filtered, and the collected solid was washed sequentially with water and EtOAc, triturated with MeOH and dried. The EtOAc-water filtrate was separated and the organic phase was washed with brine, dried and concentrated. The residue was triturated with MeOH, and the resulting solid was combined with the first solid to give ethyl 5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate as an off-white solid (1.27 g, 91% yield). Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.48 (d, J=0.9 Hz, 1H), 8.20 (br. s., 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.59 (br. s., 1H), 4.37 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), and 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: CN(C)C(=O)Cl
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N(C)C)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using dimethylcarbamyl chloride. The final product was obtained in 57% yield.