Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:14]([OH:16])=[O:15])[OH:13].CCCCCCC.C(OCC)(=O)C>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]2([C:14]([OH:16])=[O:15])[OH:13]
Reactant: O=C(O)C1(O)CCSc2c(Cl)cc(Cl)cc21
Solvent: O=CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)[C@@]1(O)CCSc2c(Cl)cc(Cl)cc21

Procedure:
The enantiomers of 6,8-dichloro-4-hydroxychromane-4-yl-carboxylic acid (2.17 g, 7.77 mmol; from step (v) above) were separated using chiral chromatography (Kromasil TBB; heptane: ethyl acetate: formic acid) affording 0.74 g of the faster moving, not wanted S-enantiomer, and 0.72 g (66%) of the slower moving sub-title compound. ee=98.4%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([N:20]([CH3:22])[CH3:21])[CH:11]=2)[OH:9])=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([N:20]([CH3:21])[CH3:22])[CH:11]=2)[O:9][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C(O)c2ccc(Cl)cc2)cc1N(C)C
Reactant: CN(C)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(C(OCCN(C)C)c2ccc(Cl)cc2)cc1N(C)C

Procedure:
A solution of the compound (1) (1.37 g, 4.26 mmol), 2-(dimethylamino)ethylchloride hydrochloride (1.84 g, 12.3 mmol) and tetrabutylammonium hydrogensulfate (145 mg, 0.43 mmol) in methylene chloride (8.5 ml) and 4N sodium hydroxide (8.5 ml) was stirred under nitrogen atmosphere at room temperature for about 60 hours. The reaction mixture was diluted with water, extracted with methylene chloride, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to recover the compound (1) (60% recovery) and to give the title compound (2). Yield 0.45 g (30%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1.O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>CCOC(C)=O.C(O)C.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)cc1-c1c(C)noc1C
Reaction time: 24 h
Yield: 100 %

Procedure:
3,5-Dimethyl-4-[2-(methyloxy)-5-nitrophenyl]isoxazole (for a preparation see Intermediate 1) (43.9 g, 177 mmol) was dissolved in EtOAc (1 liter) diluted with ethanol (1 liter) and added to Pd/C (8 g, 5% w/w, 50% water, Type E101 NO/W) in a 5 liter hydrogenation flask under vacuum, having first purged the vessel twice with vacuum/nitrogen cycles. The mixture was stirred for 24 h. No hydrogen uptake for the first 8-10 h, then steady uptake till approximately 20 liters had been consumed. The mixture purged with vacuum/nitrogen cycle×3 then was filtered through Celite™ under nitrogen and the filtrate evaporated in vacuo to give [3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine 3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)aniline (38.6 g, 177 mmol, 100% yield) as a brown crystalline solid. LCMS (formate) Rt 0.50 min, MH+ 219
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])[CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH3:57])[CH2:54][CH2:55]6)=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)c2cc(Cl)ccn2)CC1
Product: CCN1CCN(C(=O)c2cc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)ccn2)CC1
Yield: 69.1 %

Procedure:
Using 4-chloropicolinic acid chloride and N-ethylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (232 mg, 0.430 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone (120 mg, 0.473 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-ethyl-piperazin-1-yl)-methanone as a yellow solid (225 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-201) as a yellow powder (85 mg, 57%).
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1.[CH3:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=3[CH3:38])[CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Acetonitrile (10 ml) was added to the compound (1) (139 mg), 2-methylbenzyl bromide (0.03 ml), and potassium carbonate (81 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (46 mg, yield 45%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH:32]1([NH2:42])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:42][CH:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34][CH2:33]4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NC1CCCc2ccccc21
Product: O=C(NC1CCCc2ccccc21)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 1,2,3,4-tetrahydronaphthalen-1-ylamine, m.p. 163-165° C. MS [(+)ESI, m/z]: 586 [M+H]+
Reaction SMILES: Br[CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[O:37]1[CH2:38][CH2:39][N:34]([CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:35][CH2:36]1
Reactant: C1COCCN1
Reactant: CCC(Br)CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1)N1CCOCC1
Yield: 53.7 %

Procedure:
A solution of (2R)-2-[N-(4-bromohexyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid amide (Example 24; prepared as described in Reaction Scheme 1; 0.20 g, 0.44 mmol), Et3N (0.25 mL, 1.7 mmol), and morpholine (150 mg, 1.7 mmol) in CH2Cl2 (2 mL) was stirred at rt for 18 h. The reaction was then concentrated to give a crude white wax which was purified by flash chromatography (SiO2, 85% EtOAc/5% hexanes/10% MeOH) to afford the title compound (112 mg) as a white solid in 54% yield. MS (ESI), (M+H)+ 474.4; 1H NMR (DMSO-d6) δ 7.82 (d, 2H, J=8.0), 7.64 (d, 2H, J=8.0), 7.42 (br s, 1H) 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br s, 4H), 3.18-3.41 (m, 2H), 2.25-2.35 (br s, 4H), 2.27 (m, 2H) 1.15-1.62 (m, 9H), 0.80 (d, 6H, J=6.0).
Reaction SMILES: CN1CCOCC1.Cl.[C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH:17]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[CH3:18])=[CH:13][CH:12]=1)#[N:10].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](OC)[CH:34]=1)=[O:31].O>C(Cl)Cl>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH:17]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:24])[CH3:25])[NH:22][C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])[CH3:18])=[CH:27][CH:28]=1)#[N:10]
Reactant: COc1cccc(OC(=O)Cl)c1
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 13.1 %

Procedure:
1.0 g of N-methylmorpholine was added to a solution containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride dissolved in 100 ml of methylene chloride, at -20° C. After 0.9 g of 3-methoxyphenyl chloroformate was added to the mixture at -20° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred. The whole mixture was stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus yielding 0.25 g of the desired product in the form of a white plated crystal (yield: 12%).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][CH:6]=1.O1CCCC1.O.O.[OH-].[Li+]>CO>[C:23]([C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][CH:7]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]2([CH3:32])[CH3:31])#[CH:24]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
A solution of [4-(2,2,4,4-tetramethyl-8-trimethylsilanylethynyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 38, 0.13 g, 0.28 mmol) in a mixture of methanol (3 mL), tetrahydrofuran (3 mL) and water (1.5 mL) was treated with lithium hydroxide monohydrate (0.13 g, 3.1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2.5 h. The volatiles were distilled off in vacuo and the residue was diluted with water and saturated aqueous ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a white solid (0.078 g, 74%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>ClCCl>[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:23][CH2:10][O:11][CH3:12])=[C:19]([CH:22]=1)[CH:20]=[O:21]
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(C=O)cc(Br)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
Ethyldiisopropylamine (3.01 ml, 17.1 mmol) and methoxymethylchloride (1.5 ml, 15.7 mmol) were added to a dichloromethane solution (30 ml) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.3 g, 14.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→11:9). The purified product was concentrated to dryness under reduced pressure to obtain 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde (4.2 g) as light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]2([CH3:13])[O:12][CH2:11]2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2].[NH3:21]>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([OH:12])([CH3:13])[CH2:11][NH2:21])=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: CC1(C(=O)Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CO1
Reactant: N
Solvent: CO
Product: CC(O)(CN)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: -70 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
A pressure reactor was charged with 4-nitro-3-trifluoromethyl-N-[2,3-epoxy-2-methyl propionyl]aniline, BP-33, (10.0 g, 34.46 mmol) (see FIG. 3) and methanol (100 mL). After cooling to −70° C., ammonia in excess was condensed into the reactor which was sealed and stirred 14 hours. Following evaporation, the crude solid was washed with cold CH2Cl2 (50 mL). Filtration and drying gave 6.1 g BP-34 (58% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[C:5](=[O:18])[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[CH2:41][C:31]3([C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30][C:27]2=[N:28][CH:29]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[C:5](=[O:18])[N:6]([CH2:14][C:15]([NH:23][C:24]2[CH:25]=[C:26]3[CH2:41][C:31]4([C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:33][C:32]4=[O:40])[CH2:30][C:27]3=[N:28][CH:29]=2)=[O:17])[C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)Nc1nc(Cl)c(-c2ccccc2)n(CC(=O)O)c1=O
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Nc1nc(Cl)c(-c2ccccc2)n(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [5-chloro-3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl]acetic acid (74 mg, 0.23 mmol) [Parlow et al. (2003) J. Med. Chem. 46, 4050], (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol) [Wood et al. US 2007/265225], N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-])=O)=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C.O>[NH2:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:5]([CH3:16])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)N1CCOCC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1cc(N)c(Cl)cc1C(=O)N1CCOCC1
Temperature: 65 °C
Yield: 92.7 %

Procedure:
To (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 0.86 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (776 mg, 3.44 mmol). The mixture was heated to 65° C. for 5 h and then 2 M aqueous sodium hydroxide solution (10 mL) and DCM (10 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (203 mg, 93%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=255 at 2.84 min. 1H NMR (400 MHz, CDCl3): δ 7.07 (s, 1H), 6.60 (s, 1H), 4.10 (br s, 2H), 3.84-3.53 (br m, 6H), 3.36-3.24 (br m, 2H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[CH:12]=[C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[NH:16][C:10]3=[CH:9][C:8]=2[C:7]([CH3:26])([CH3:25])[C:6]1=O)[CH2:2][CH2:3][CH3:4].N#N.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH2:1]([N:5]1[C:13]2[CH:12]=[C:11]3[N:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[NH:16][C:10]3=[CH:9][C:8]=2[C:7]([CH3:25])([CH3:26])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCN1CC(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
To a solution of 5-butyl-2-(4-methoxy-phenyl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg) in dry THF (10 ml) under an inert atmosphere (N2) is added LiAlH4 (31.4 mg; 826 μmol). The reaction mixture is refluxed for 6 h and afterwards stirred at RT for another 15 h. Excess LiAlH4 is carefully hydrolyzed with NaOH solution (1 M; 30 ml). The aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired compound (140 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([C:25](=[O:30])N(OC)C)=[CH:24][C:19]3=[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:17]=2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[CH3:45])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].S([O-])(O)(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([CH:25]=[O:30])=[CH:24][C:19]3=[C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:17]=2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[CH3:45])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C=O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 2.5 °C
Reaction time: 3.5 h
Yield: 40.5 %

Procedure:
To a solution of the compound of step 1 (0.990 g, 1.61 mmol) in 11 ml of anhydrous THF, cooled to 0° C. under an atmosphere of nitrogen, was added a 1 M solution of lithium tri-tert-butoxy-aluminium hydride in THF. The mixture was stirred at 0-5° C. for 3.5 h. Then a 0.5 M aqueous solution of potassium hydrogensulfate (20 ml) was added, the mixture was vigorously stirred for 1 min and then extracted twice with EA (30 ml). The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate (20 ml) and brine (40 ml), dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (cyclohexane/EA, 70:30, then 65:35) to give 0.363 g of the title compound as a yellow solid melting at 208-209° C.
Reaction SMILES: [K+].[Br-].[CH3:3][O:4][C:5]([C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)=[CH:9][CH:8]=1)=[O:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:17]=[C:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][O:11][C:10]2[CH:22]=[CH:23][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8][C:9]1=2
Reactant: COC(=O)c1ccc(OCc2ccccc2C(=O)O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
IR (KBr disk): 3400, 1700, 1610, 1260, 1235 cm-1The thus obtained 2-(4-methoxycarbonylphenoxy) methyl benzoic acid (392.7 g) is suspended in 5.0 l of methylene chloride and 266.0 g of trifluoroacetic anhydride is added thereto. After stirring the mixture at room temperature for one hour, 19.4 g of boron trifluoride-ethylether complex is added thereto and the mixture is stirred at room temperature for two hours. The reaction solution is poured into ice water. After an organic solvent layer is separated from the mixture, the organic layer is washed with diluted aqueous sodium hidroxide solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 335.3 g of methyl 11-oxodibenz[b,e]oxepin-2-carboxylate as a white crystal.
Reaction SMILES: C12(COC3C=CC(C(N)=O)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:53][CH2:52]4)=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.CS(Cl)(=O)=O.[O:60]1[CH2:64][CH2:63][CH:62]([S:65](Cl)(=[O:67])=[O:66])[CH2:61]1>>[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:52][CH2:53]4)=[CH:49][C:45]([C:46]([NH:48][S:65]([CH:62]4[CH2:63][CH2:64][O:60][CH2:61]4)(=[O:67])=[O:66])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: O=S(=O)(Cl)C1CCOC1
Agent: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)C1CCOC1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride, the title compound was obtained as a colorless solid (0.14 g, 28%): 1H NMR (300 MHz, CDCl3) δ8.72-8.60 (m, 1H), 7.60-7.53 (m, 1H), 6.63-6.53 (m, 1H), 4.62-4.48 (m, 1H), 4.33-4.23 (m, 1H), 4.16-3.82 (m, 3H), 3.56 (s, 2H), 2.58-2.44 (m, 1H), 2.42-2.26 (m, 1H), 2.10-1.99 (m, 4H), 1.84-1.66 (m, 12H), 1.00-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 478.1 (M+1).