Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ccccc2N)cc1

Procedure:
0.700 g of a suspension of [4-(2-nitro-phenylamino)-phenyl]-acetic acid methyl ester and 0.240 g of Pd/C (10%) in 20 ml of MeOH is stirred for 3 hours at rt under a hydrogen atmosphere. The mixture obtained is filtered through a pad of Celite and the filtrate obtained is concentrated. [4-(2-Amino-phenylamino)-phenyl]-acetic acid methyl ester is obtained in the form of an oil: ES-MS: 257.1 [M+H]+; single peak at tR=3.04 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.[NH:52]([CH2:55][CH3:56])[CH2:53][CH3:54].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=1
Reactant: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3C=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccccc1CS(=O)(=O)NCCc1c(CCCc2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 41.3 %

Procedure:
As outlined in Example 17, Step 1 methyl 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (Example 16, Step 5, 58 mg, 0.081 mmol) was reacted with HNEt2 (0.022 mL, 0.21 mmol) and NaBH(OAc)3 (56 mg, 0.26 mmol) in DCE (2 mL) to afford methyl 4-{3-[5-chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate (26 mg, 41%) and the side product methyl 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(hydroxymethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoate (8.6 mg, 15%), both as white solids.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:64][CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]1>>[NH:61]1[CH2:62][CH2:63][CH2:64][CH:58]([NH:57][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:59][CH2:60]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and tert-butyl 4-aminoazepane-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.65 (m, 4 H) 1.65-1.83 (m, 3 H) 1.83-1.99 (m, 4 H) 2.07 (m., 2 H) 3.16 (s, 3 H) 3.32 (s, 3 H) 3.93 (s, 3 H) 4.07 (t, J=13.8 Hz, 3 H) 4.78 (t, J=8.1 Hz, 1 H) 7.41-7.54 (m, 2 H) 8.14-8.29 (m, 2 H) 8.31 (d, J=7.6 Hz, 1 H) 8.55 (br. s., 2 H). [M+H] calc'd for C27H35F2N7O3, 544; found 544.
Reaction SMILES: O[CH:2]([C:5]1[C:6]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:7][N:8](C)[C:9]=1C(C)(C)C)[CH2:3][CH3:4].F[C:20](F)(F)C(O)=O>>[CH2:2]([C:5]1[CH:9]=[N:8][N:7]([CH3:20])[C:6]=1[S:15]([NH2:18])(=[O:17])=[O:16])[CH:3]=[CH2:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(O)c1c(S(N)(=O)=O)nn(C)c1C(C)(C)C
Product: C=CCc1cnn(C)c1S(N)(=O)=O
Temperature: 25 °C

Procedure:
The alcohol (3.0 g) from Example 3 was stirred in 25 ml of trifluoroacetic acid at 68° C. for 30 minutes. The solution was allowed to cool to room temperature, and the volatile components were removed in vacuo to afford 510 mg of the desired sulfonamide, m.p. 157°-161° C.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][C:15]=1[CH3:32].C(N=C=NC(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:7][O:8][C:29]([C:23]2[C:24](=[O:28])[NH:25][C:26](=[O:27])[N:21]([C:17]3[CH:18]=[C:19]([CH3:20])[C:14]([O:13][C:12]4[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:10]([Br:9])[CH:11]=4)=[C:15]([CH3:32])[CH:16]=3)[N:22]=2)=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)OCC4CCCCC4)c(=O)[nH]c3=O)cc2C)cc1Br
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of cyclohexylmethanol (9 μmol) in DMF were added sequentially solutions of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (5 μmol), diisopropylcarbodiimide (10 umol) and 4-dimethylaminopyridine (10 μmol). The resulting solution was shaken at 50° C. for 18 h. HPLC and LCMS shows the starting material to be consumed and the desired product present. MS Calc.: 557.1; Found: 556.1 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=O)=[CH:15]2)(=[O:8])=[O:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])#[N:21]
Reactant: NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.65 g) and pyridine (20 mL) was slowly added trifluoroacetic anhydride (4.50 mL) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with tetrahydrofuran-hexane (2:3, volume ratio). The eluate was treated with activated carbon and concentrated to give the title compound (4.04 g, yield 92%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 283-284° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: BrCCCCCBr
Reactant: Cc1ccc(CCO)cc1
Product: Cc1ccc(CCOCCCCCBr)cc1

Procedure:
(17.9 g) as a colourless oil, from 4-methylbenzeneethanol (10.0 g) and 1,5-dibromopentane (50.7 g) with stirring at room temperature for 72 h. T.l.c. (ER-CX 1:19) Rf 0.29.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(NCC)C.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[N:3][CH:4]=1
Reactant: C#CCO
Reactant: Brc1ccc(Br)nc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(Br)cn1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
Copper (I) iodide (10 mg) was added to a solution of 2,5-dibromopyridine (4.74 g), propargyl alcohol (1.34 g) and BTPC (75 mg) in diethylamine (50 ml) and the mixture stirred overnight (18 h), under nitrogen. The solution was evaporated in vacuo and the residue treated with 8% sodium bicarbonate (50 ml) and partitioned with dichloromethane (3×50 ml). The combined extracts were dried and evaporated and the residual semi-solid purified by FCC. Eluting with ether afforded the title compound (3.43 g) as fawn crystals m.p. 121°-122°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH:22]=[C:21]([O:23][CH3:24])[C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COc1cc(CCl)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1cc(OC)c(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (585 mg) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 115 mg) at 0° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave methyl E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (970 mg, yield 65%) as a colorless oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH:16]([C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[O:17][C:18]1[CH:42]=[CH:41][C:21]([C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:25]=2)=[O:23])=[CH:20][CH:19]=1)([OH:15])=O.[CH2:53]([C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1)[CH:54]([CH3:56])[CH3:55].ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:49]([C:46]1[CH:47]=[CH:48][C:43]([CH:16]([C:13](=[O:15])[NH:61][C:60]2[CH:62]=[CH:63][C:57]([CH2:53][CH:54]([CH3:56])[CH3:55])=[CH:58][CH:59]=2)[O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:25]=3)=[O:23])=[CH:41][CH:42]=2)=[CH:44][CH:45]=1)[CH:50]([CH3:51])[CH3:52]
Reactant: CC(C)Cc1ccc(N)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)O)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)Nc3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg) was added to a mixture of ethyl 4-[3-[4-[(carboxy)(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (70 mg), 4-isobutylaniline (20 mg) and 1-hydroxybenzotriazole (20 mg) in dichloromethane (3 ml). After stirred at 25° C. for 4 hours, the mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (5 g) eluting with chloroform to give ethyl 4-[3-[4-[(4-isobutylphenyl)[(4-isobutylphenyl)carbamoyl]methoxy]benzoyl]indol-1-yl]butyrate (85 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@@H:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[C@H:27]([O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:18][C:19]=1[CH3:25])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (5.0 g, 12.1 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (3.3 g, 18.3 mmol), and triphenylphosphine (4.8 g, 18.3 mmol) in anhydrous benzene (50 mL) at room temperature under nitrogen was added dropwise diethyl azodicarboxylate (2.6 mL, 18.3 mmol) over a period of 25 min. The reaction mixture was heated for 2 h, then stirred at room temperature for 3 days. The crude reaction mixture was adsorbed onto silica gel and chromatographed twice with petroleum ether:ethyl acetate (95:5) to yield the title compound as a white foamy solid (4.5 g, 65%): NMR (DMSO-d6): δ8.18 (d, 1H), 7.64 (ddd, 1H), 7.53-7.43 (m, 2H), 7.38-7.24 (m, 5H), 7.00 (s, 2H), 4.80 (t, 1H), 3.58 (s, 3H), 3.31 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.55 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 572/574; Anal. Calc. for C32H29BrO3S: C, 67.01; H, 5.10; N, 0.00. Found: C, 66.33; H, 5.09; N, 0.09; Analytical HPLC indicates a major component (94.39%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(Cl)CCl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NC1CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (300 g, 1.4 mol) in DCM (8.4 L) at rt was added cyclopropanamine (79.64 g, 1.4 mol) and EDC (320.9 g, 1.67 mol) in one portion. After stirring overnight, the solution was washed with water and the aqueous phase was reextracted with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The remaining solid was triturated with diisopropyl ether, filtered, washed and dried in vaccuo to yield 260 g (73.4%) 4-bromo-N-cyclopropyl-2-methylbenzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH:18]3[CH:14]([N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][CH:11]1[CH:18]2[CH:14]([NH:15][CH2:16][CH2:17]2)[CH2:13][CH2:12]1)=[O:9].[C:28]([OH:30])([C:27]([F:32])([F:31])[F:26])=[O:29]
Reactant: Cc1cncc(C(=O)NC2CCC3C2CCN3C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(C(=O)NC2CCC3NCCC32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 50 mL round bottom flask was charged with a magnetic stirbar, Compound 12 (1.5 g, 6.11 mmol) and dichloromethane (25 mL). Trifluoroacetic acid (2.1 g, 18.3 mmol) was added and the reaction mixture was allowed to stir at room temperature for 4 hours. Solvent and volatiles were removed in vacuo overnight to yield Compound 13 as its TFA salt.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21](Br)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: CCCCC(Br)CCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCCCCCCCBr)cccc21

Procedure:
Potassium phthalimide (1 g; 5.4 mmoles) was added to a solution of 1,8-dibromododecane (5.31 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: C[Mg]Br.[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[C:5]1=[O:14])[CH2:11]2.[CH2:15](Cl)Cl>C(OCC)C.O1CCCC1>[CH3:15][C:5]1([OH:14])[CH:6]2[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][CH:4]1[CH2:11]3)[CH2:7]2
Reactant: ClCCl
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
110 ml of a solution of methyl magnesium bromide (3.0 M) in diethyl ether was diluted with 100 ml of anhydrous tetrahydrofuran (THF). Then, the solution was put into a 1 liter flask and then maintained at 0° C. 2-adamantanone (45 g, 0.3 mol) was dropped slowly using a dropping funnel and then the reaction was stirred at room temperature for about 12 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then the resultant product was poured into water. Then, the resultant product was neutralized with dilute sulfuric acid and extracted using diethyl ether and was then dried over magnesium sulfate. The obtained crude product was recrystallized using n-hexane and a methylene chloride cosolvent to yield the desired product 2-methyl-2-adamantanol (yield: 80%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCO>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:24]1[CH2:23][CH2:22][CH:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1)=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h

Procedure:
4.4 mL (40.6 mmol) ethyl acrylate were added to a solution of 10.0 g (37.3 mmol) tert-butyl[4,4′]bipiperidinyl-l-carboxylate in 100 mL EtOH and the reaction mixture was refluxed for 2 h. To complete the reaction a further 1 mL (9.2 mmol) of ethyl acrylate were added, the mixture was refluxed for 1 h and left overnight at RT. The solvent was eliminated i. vac. and the crude product was further reacted without being purified.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]1[OH:13].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:22][S:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]1[OH:13]
Reactant: O=C([O-])[O-]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(S)ncnc32)[C@@H](O)[C@@H]1O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
6-mercapto-9-(β-D-arabinofuranosyl)purine is reacted at room temperature with methyl iodide in dimethyl sulphoxide in the presence of anhydrous potassium carbonate to give 6-methylthio-9-(β-D-arabinofuranosyl)purine, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[CH:19]=[C:20]([C:22](Cl)=[O:23])[CH3:21].[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:25]([NH:28][C:12](=[O:13])[C:11]1[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:19]=[C:20]([C:22](=[O:23])[NH:8][CH2:5][CH2:4][CH3:3])[CH3:21])[CH:4]=1)=[O:18])[CH2:26][CH3:27]
Reactant: CCCN
Reactant: CC(=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)Cl
Solvent: CCOC(C)=O
Product: CCCNC(=O)C(C)=Cc1cc(NC(=O)C2=C(C(=O)NCCC)CCCC2)ccc1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 10.9 g of N-[4-chloro-3-(2-chlorocarbonylprop-1-en-1-yl)-phenyl]-3,4,5,6-tetrahydrophthalimide in 200 ml of ethyl acetate was added dropwise to a solution of 5.9 g of n-propylamine in about 150 ml of ethyl acetate while cooling with ice. The mixture was stirred for 3 hours at about 20° C., after which the solid formed was separated off, washed twice with 5% by weight aqueous hydrochloric acid and then once with petroleum ether and then dried under reduced pressure at 40° C. The crude product was recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[C:3](=[O:7])[CH:4]=[CH:5][CH3:6].[C:10]([OH:13])(=[S:12])[CH3:11]>N1CCCCC1>[C:10](=[O:13])([S:12][CH:5]([CH2:4][C:3](=[O:7])[CH:2]([CH3:1])[CH2:8][CH3:9])[CH3:6])[CH3:11]
Reactant: CC(O)=S
Reactant: CC=CC(=O)C(C)CC
Solvent: C1CCNCC1
Product: CCC(C)C(=O)CC(C)SC(C)=O
Temperature: 15 °C
Yield: 89.5 %

Procedure:
A reaction flask was charged with 5-methyl-2-hepten-4-one (200 g, 1.59 mol) and piperidine (6.6 g), and cooled to 15° C. using a cooling bath. Thioacetic acid (241 g, 3.17 mol) was subsequently added to the reaction flask dropwise through an addition funnel The feeding was exothermic. The reaction temperature was kept below 25° C. After the addition was completed, the cooling bath was removed while the reaction was stirred for another hour at room temperature. The reaction mixture was then transferred into a separatory funnel. The organic layer was washed with sodium bicarbonate solution (10%, 250 mL) followed by brine (250 mL), and dried with magnesium sulfate. Further distillation of the obtained crude product under a vacuum (at 78° C. with a pressure of 11.0 mmHg) provided S-(5-methyl-4-oxoheptan-2-yl) ethanethioate (288.0 g) (about 90% yield with a purity over 97% monitored with gas chromatography).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: Cc1cccc(F)c1B(O)O
Product: Cc1cccc(F)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-methylphenyl)boronic acid gave 273. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.74 (s, 1H), 7.45-7.33 (m, 3H), 7.26-7.14 (m, 2H), 5.02-4.77 (m, 2H), 4.10-3.85 (m, 2H), 3.75 (s, 3H), 3.37 (s, 3H), 2.15-2.04 (m, 1H), 1.98-1.75 (m, 2H), 1.72-1.63 (m, 1H). LCMS (ES+) m/z 463 (M+1).