Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([CH:47]=1)[C:44]([OH:46])=[O:45].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:14]=[C:13]3[C:39]2[CH:40]=[N:41][CH:42]=[C:43]([CH:47]=2)[C:44]([OH:46])=[O:45])=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C(=O)O)c3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (4.0 g, 7.662 mmol) and 5-bromonicotinic acid (2.3 g, 11.49 mmol, Sigma-Aldrich) in DME (75 mL)/water (18 mL) was added Na2CO3 (2.7 g, 22.98 mmol) and Pd(PPh3)4 (878 mg, 0.76 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product (3.0 g), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 518.2 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:28]2[CH2:27][CH2:26][C@H:25]3[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@@H:20]([C:19]5[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[C:28]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@H]21
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 85 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 85% of theory; LC (method 1): tR=2.62 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [O:1]([C@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:22][C@@H:23]1[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]([O:22][C@@H:23]1[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:26]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:25][C@H:24]1[N:47]1[C:48]2[N:49]=[C:50]([Cl:57])[N:51]=[C:52]([NH:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:53]=2[N:54]=[CH:55]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCC[C@@H]1Oc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@@H]4Oc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 50 h
Yield: 94.7 %

Procedure:
cis-2-Phenoxycyclopentylamine (0.75 g, 4.23 mmol) was combined with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.95 g, 4.7 mmol) and triethylamine (0.64 g, 6.3 mmol) in dioxan (30 ml) and stirred for 50 h. The reaction mixture was filtered, evaporated and the residue dissolved in ethyl acetate and washed with water (2×50 ml). The organic phase was dried (MgSO4), evaporated and the residue coevaporated to give cis-2',3',5'-tri-O-benzoyl-2-chloro- N-(2-phenoxycyclopentyl)adenosine (3.1 g, 90%) as an amorphous foam, which was deprotected using saturated methanolic ammonia (50 ml). After 70 h at room temperature the reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1). The title cis-2-chloro- N-(2-phenoxycyclopentyl)adenosine (0.925 g, 53%) was obtained as an amorphous foam (a 1:1 mixture of diastereoisomers), 1H NMR (DMSO-d6)δ 1.58-2.15 (6H, 3m, --CH2CH2CH2 --), 3.51-3.60 (1 H, m, H-5'a), 3.62-3.71 (1H, m, H-5'b), 3.95 (1H, br q, H-4'), 4.12 (1H, br q, H-3'), 4.46-4.62 (2H, m, H-2' and --CH), 4.82-4.89 (1H, m, --CH), 5.07 (1H, br t, 5'-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 6.80-6.91 (3H, m, Ar--H), 7.15-7.24 (2H, t, Ar--H), 7.99, 8.22 (1H, d & m, N--H), 8.41, 8.45 (1 H, 2s, H-8).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:34]3=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]3[CH:32]=[N:31]2)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:24]4[CH2:29][CH2:28][CH:27]([N:30]5[C:34]6=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]6[CH:32]=[N:31]5)[CH2:26][CH2:25]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CC1
Yield: 41.9 %

Procedure:
300 mg (1 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde and 306 mg (1.20 mmol) 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine were reacted for four days (additional NaBH(OAc)3 has been added after four, six, eight, 24 and 28 hours (two equivalents each)) at room temperature and purified as previously described. 210 mg of the desired compound were obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc2ccccc2c1Br
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc2ccccc2c1-c1ccccc1F
Yield: 60 %

Procedure:
Into a 500 mL three-neck flask were placed 8.7 g (35 mmol) of 1-bromo-2-methoxynaphthalene, and 5.0 g (35 mmol) of 2-fluorophenylboronic acid. The air in the flask was replaced with nitrogen. To this mixture were added 120 mL of toluene, 60 mL of ethanol, and 40 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 2.0 g (1.7 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for 8 hours under a nitrogen stream. The aqueous layer of the obtained mixture was subjected to extraction with toluene, and the obtained solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. An oily substance obtained by concentration of the obtained filtrate was dissolved in about 30 mL of toluene. This solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). An oily substance obtained by concentration of the obtained filtrate was dried under reduced pressure, so that 5.3 g of a pale yellow oily substance of the object of the synthesis was obtained in 60% yield. The reaction scheme of Step 1 is illustrated in (E2-1).
Reaction SMILES: [C@@H:1]1([C:7]([OH:9])=[O:8])[O:3][C@@H:2]1[C:4]([OH:6])=[O:5].[OH-:10].[Mg+2:11].[OH-]>>[C:7]([C@@H:1]([C@H:2]([C:4]([O-:6])=[O:5])[OH:10])[OH:3])([O-:9])=[O:8].[Mg+2:11]
Reactant: O=C(O)[C@H]1O[C@H]1C(=O)O
Reactant: [OH-]
Agent: [Mg+2]
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 35 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
In 100 ml of an aqueous solution containing 1.0 g of cis-epoxysuccinic acid and 0.44 g of magnesium hydroxide and adjusted to pH value of 8.0, a 0.5 g portion of clean microbic cells of Acetobacter curtus No. 4 (FERM-P No. 2879) obtained by following the procedure of Example 3 was added and shaken at 35° C for 5 hours. In the reaction mixture, there was formed magnesium L(+)-tartrate. The amount of the salt thus produced was 1.19 g and the yield was 91 percent. By treating this product with a column packed with Amberlite IR 120 (H+ type cation-exchange resin) similarly to Example 3, there was obtained L(+)-tartaric acid. This L(+)-tartaric acid was found to have an optical purity of 100 percent.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:28][CH2:27]3)=[C:22]([C:23]#[N:24])[CH:25]=2)=[O:16])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1Cc1ccccc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1Cc1ccccc1
Yield: 22.9 %

Procedure:
The reaction and treatment in the same manner as in Example 64 were conducted using 1-benzyl-5-methylpyrazole-4-carboxylic acid (0.7 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.93 g) and the resulting product was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (0.36 g), melting point: 155° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[N:10][C:9]([Br:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=2)=[N:10][C:9]([Br:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:25]=[N-:26]
Reactant: COC(=O)c1cc(Br)nc(-c2cccc(CO)c2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cc(Br)nc(-c2cccc(C=O)c2)c1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Methyl 3-amino-6-bromo-2-(3-(hydroxymethyl)phenyl)isonicotinate (1.35 g, 4.00 mmol) was dissolved in TFA (20 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (0.553 g, 8.01 mmol) was added with stirring to give a yellow solution with gas evolution. After 30 min, sodium azide (2.60 g, 40 0 mmol) was added over 5 min followed immediately by Et2O (20 mL). A precipitate formed and, after 0.5 hr, water was added and the mixture was extracted with EtOAc. The organic phases were washed with water (3×), brine (1×), and then saturated Na2CO3 solution (until the aqueous phase was basic) and brine (1×). After drying with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with DCM containing 20% hexane, DCM and DCM containing 5% EtOAc) afforded methyl 3-azido-6-bromo-2-(3-formylphenyl)isonicotinate (0.90 g, 2.5 mmol, 63% yield) as a tan solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.09 (1H, s), 8.27 (1H, t, J=1.51 Hz), 8.01-8.07 (1H, m), 7.98 (1H, ddd, J=7.68, 1.51, 1.38 Hz), 7.84 (1H, s), 7.65 (1H, t, J=7.68 Hz), 4.02 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][N:24]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of methyl 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzoate was dissolved in 20 ml of tetrahydrofuran and 10 ml of methanol, and 2.6 ml of 2N aqueous sodium hydroxide solution were added. After one hour of stirring at room temperature, 2.6 ml of 2N hydrochloric acid were added, and the reaction mixture was concentrated under reduced pressure. Saturated sodium chloride solution and ethyl acetate were added to the residue, and the mixture was shaken. The ethyl acetate phase was isolated, dried and concentrated. The resulting crude product was purified chromatographically. Yield: 0.91 g (94%)
Reaction SMILES: [CH3:1][S:2][C:3]([S:22][CH3:23])=[N:4][CH2:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C:11]2([CH2:16][CH2:15]3)[CH2:10][S:9]1(=[O:21])=[O:20])=[O:7].C([Li])CCC.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.I[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]=[CH2:55]>O1CCCC1>[CH3:23][S:22][C:3]([S:2][CH3:1])=[N:4][CH:5]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]=[CH2:55])[C:6]([N:8]1[CH:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C:11]2([CH2:16][CH2:15]3)[CH2:10][S:9]1(=[O:20])=[O:21])=[O:7]
Reactant: C=Cc1ccccc1CI
Reactant: CSC(=NCC(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C)SC
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccccc1CC(N=C(SC)SC)C(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
Dissolve 2-(bis-methylsulfanyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.0 1,5)dec-4-yl)-ethanone (7.91 g, 21.0 mmol) in tetrahydrofuran (100 mL) and cool to −78° C. Treat, by dropwise addition, with 1.6 M n-butyllithium in hexane (13.1 mL, 21 mmol). Stir for 1.5 hours, then add hexamethylphosphotriamide (HMPA) (4.25 mL, 24.4 mmol). Stir for 15 minutes and add, via cannula, a solution of 1-iodomethyl-2-vinyl-benzene (6.1 g, 25 mmol) in tetrahydrofuran (100 mL). Stir overnight at room temperature, partition between saturated ammonium chloride (2×75 mL) and ethyl acetate (400 mL). Dry (Na2SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give 2-(bis-methylsulfanyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.0 1,5)dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one as a white solid (4.5 g).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (3.29 g, 21.0 mmole) and pyridine (1.74 g, 22.0 mmole) were added to a solution of tryptamine (3.2 g, 20.0 mmole) in CH2Cl2 and stirred for 24 h at room temperature. Working up was performed by extracting the batch successively with water, with 1M HCl and with 1M NaOH. The organic phase was dried with Na2SO4 and evaporated. The product was obtained as a colorless solid (m.p. 44-46° C.) in a yield of 5.58 g (100%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CCNS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
Methanesulfonyl chloride (0.082 mL, 1.05 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (300 mg, 1.05 mmol) and N,N-diisopropylethylamine (0.367 mL, 2.11 mmol) in DCM (4 mL) at 20° C. The resulting solution was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and diluted with Et2O (25 mL) and washed with water (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamate (275 mg, 71.9%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]1[C:57]2[C:52](=[CH:53][C:54](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:56]=2)[CH2:51][CH2:50]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:54]3[CH:53]=[C:52]4[C:57](=[CH:56][CH:55]=3)[CH2:49][CH2:50][CH2:51]4)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3)OC1(C)C
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCC2
Temperature: 100 °C
Yield: 69.4 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran (106) (580 mg, 0.8 mmole) in toluene/EtOH (9 mL/8 mL) were added 2-(2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (121) (400 mg, 1.6 mmol), tetrakis(triphenylphosphin)palladium (180 mg, 0.16 mmol), and Cs2CO3 (2.1 g, 2.32 mmol) at room temperature. The mixture was stirred at 100° C. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the title compound (425 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH:13]1([N:7]2[CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:6]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2
Yield: 61.6 %

Procedure:
A mixture of 0.053 g (0.0002 mole) of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10), 0.04 g (0.00024 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.049 g of 4-(9-cyclopentyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[O:38][C:37](=[O:39])[CH2:36][C:35](=[O:40])[CH2:34]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[O:38][C:37](=[O:39])[CH:36]([CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[C:35](=[O:40])[CH2:34]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: Cn1ccnc1C=O
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 1-methyl-1H-imidazole-2-carbaldehyde was substituted in place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in that example.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>CN(C=O)C>[N:1]1([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCNC1
Solvent: CN(C)C=O
Product: c1ccc2oc(N3CCCNCC3)nc2c1
Reaction time: 1 h

Procedure:
A 978 mg portion of homopiperazine was dissolved in 3 ml of DMF. Under cooling with ice, 500 mg of 2-chloro-benzoxazole was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 24 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in 200 ml of ethyl acetate, washed with sodium hydrogencarbonate aqueous solution (pH 8) and water in that order, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain 540 mg of the title compound.