Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC1C=CC=CC=1)C1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[O:47]1[CH2:50][C:49](CN)([CH2:51][NH2:52])[CH2:48]1>>[NH2:52][CH2:51][C:49]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:50][O:47][CH2:48]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCC1(CN)COC1
Product: NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccccc23)COC1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.32 (d, J=2.1 Hz, 1 H), 8.11 (t, J=2.0 Hz, 1 H), 8.04 (d, J=1.9 Hz, 1 H), 7.93 (d, J=2.0 Hz, 1 H), 7.77 (m, J=8.3 Hz, 2 H), 7.63 (t, J=3.7 Hz, 1 H), 7.53 (d, J=3.8 Hz, 1 H), 6.30 (s, 1 H), 5.45 (s, 2 H), 4.65 (m, J=5.5 Hz, 6 H), 4.01 (s, 2 H), 3.83 (t, J=2.4 Hz, 2 H), 3.51 (s, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19][CH2:20][C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](OC(N1CCC(CCOC[C@@H](O)C(O)=O)CC1)=O)[C:27]1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19][CH2:20][C@@H:21]([OH:25])[C:22]([O:24][CH2:26][CH3:27])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](O)CSCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)[C@H](O)COCCC1CCN(C(=O)OCc2ccccc2)CC1
Product: CCOC(=O)[C@H](O)CSCCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
3.7 g of 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethylthio]-2(S)-hydroxypropionic acid, in place of 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethoxy]-2(R)-hydroxypropionic acid, is subjected to the same reaction and treatment procedures as in Reference Example 9 to give 2.0 g of oily ethyl 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethylthio]-2(S)-hydroxypropionate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Brc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromoaniline (Aldrich; 1.3 equiv.) in methanol (0.4 M) was treated with 3-pyridinecarboxaldehyde (Aldrich; 1.0 equiv.). The solution was heated to reflux for 2 hours. The reaction was cooled to 0° C. and treated slowly with sodium borohydride (3.4 equiv.). After 1 hour the cooling bath was removed and stirring continued overnight. The reaction was concentrated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was back-extracted once with DCM. The combined organics were washed with water and brine. The organic layer was concentrated to a white solid, which was purified via recrystallization from 1.2:4 ethyl acetate/hexanes to give the title compound. Anal Calcd for C12H11BrN2.0.1H2O: C, 54.40; H, 4.26; N, 10.57. Found: C, 54.30; H, 4.12; N, 10.44. MS found 262.84, 264.83 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]3([O:15][CH:8]3[C:7]=2[CH:16]=1)O)#[N:2].[CH2:17]([NH2:20])[CH2:18][NH2:19]>C(O)C>[NH2:19][CH2:18][CH2:17][NH:20][C@@H:8]1[C:7]2[CH:16]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:12])([CH3:13])[C@H:9]1[OH:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21O
Reactant: NCCN
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCCN)[C@@H]1O
Yield: 77.8 %

Procedure:
A mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-3-ol (0.927g) and ethylenediamine (2.78g) was heated under reflux in ethanol (70 ml) for 16 h. The solvent was evaporated in vacuo and the residue column chromatographed (Kieselgel 60, gradient elution: 0-9% 880 ammonia-methanol) giving the title compound (0.868g) as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24]([OH:26])=O)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH2:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH:36][C:24]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[C:11]=1[CH:21]([CH3:23])[CH3:22])=[O:26]
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ncco3)c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 42, 244 mg, 0.685 mmol) in CH2Cl2 (12 ml) was added EDC (262 mg, 1.37 mmol) and DMAP (125 mg, 1.03 mmol), followed by 3,4-difluorobenzyl amine (197 mg, 1.03 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C@H:7]2[CH2:8][C@@H:9]3[O:21][CH:22]([O:23]C)[C@@:6]2([C@@H:11]2[CH2:12][CH2:13][C@H:14]4[C:17]([C:19](=[O:20])[C@@:10]32[C@@H:15]4[OH:16])=[CH2:18])[C@@H:5]([OH:25])[CH2:4][CH2:3]1>CCCCCC.C(OC(=O)C)C>[CH3:1][C:2]1([CH3:26])[C@H:7]2[CH2:8][C@@H:9]([OH:21])[C@@:10]34[C:19](=[O:20])[C:17](=[CH2:18])[C@@H:14]([C@H:15]3[OH:16])[CH2:13][CH2:12][C@H:11]4[C@:6]2([CH2:22][OH:23])[C@@H:5]([OH:25])[CH2:4][CH2:3]1
Reactant: C=C1C(=O)[C@@]23[C@@H]4C[C@@H]5C(C)(C)CC[C@H](O)[C@@]5(C(OC)O4)[C@@H]2CC[C@@H]1[C@H]3O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C1C(=O)[C@@]23[C@H](O)C[C@@H]4C(C)(C)CC[C@H](O)[C@@]4(CO)[C@@H]2CC[C@@H]1[C@H]3O

Procedure:
The third fraction obtained by the first silica gel column chromatography was loaded on the third silica gel column chromatography, and four fractions, 3-A, 3-B, 3-C and 3-D, were obtained by elution with hexane-ethylacetate step gradient system. Kamebacetal A represented by Chemical Formula 2 was isolated from the 3-B fraction, and kamebakaurin represented by Chemical Formula 3 was isolated from the 3-C fraction.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]#[N:26])[CH:24]=4)[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:31]O.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]([NH2:26])=[O:31])[CH:24]=4)[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C#N)c2[nH]1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C(N)=O)c2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-yl)-cyclopropanecarboxamide (45 mg, 0.11 mmol) was suspended in a mixture of methanol (1.8 mL), 30% aqueous hydrogen peroxide (0.14 mL, 4.4 mmol) and 10% aqueous sodium hydroxide (0.150 mL). The resulting suspension was stirred for 72 h at room temperature. The hydrogen peroxide was then quenched with sodium sulfite. The reaction mixture was diluted with 0.5 mL of N,N-dimethylformamide, filtered, and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-2-tert-butyl-1H-indole-7-carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)+. Retention time of 1.74 minutes.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[C@H:28]([OH:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@@H:28]([OH:32])[C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)[C@@H](O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)[C@@H](O)C(F)(F)F

Procedure:
The title compound, white solid (17 mg, 54.7%), MS (ISP) m/z=457.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and (R)-3,3,3-trifluoro-2-hydroxypropanoic acid
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2cccc3c(N)c(C(=O)NC4CCC4)nnc23)c1
Yield: 37.7 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 3,5-dimethylphenyl boronic acid (169 mg) were reacted to afford the title compound (59 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.31 (d, 1H), 8.38 (d, 1H), 7.78 (m, 2H), 7.28 (s, 2H), 7.06 (s, 1H), 4.52 (m, 1H), 2.35 (s, 6H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=347 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:17]([Br:36])=[C:16]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=3)[N:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1CCN(c2cc(Oc3cc(C(F)(F)F)nn3C)ncn2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncnc(Oc3cc(C(F)(F)F)nn3C)c2Br)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester (150 mg, 0.37 mmol) and NBS (65 mg, 0.37 mmol) in DMF (3 ml) was stirred at 60° C. for 2 days. The mixture was quenched with sodium thiosulfate, and extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (hexanes:ethyl acetate=3:1) provided compound A19 as a white solid (100 mg, 57%). 1HNMR (CDCl3, 400 MHz) δ 1.28 (t, 3H), 1.78-1.88 (m, 2H), 1.95-2.05 (m, 2H), 2.57-2.62 (m, 1H), 3.17 (t, 2H), 3.81 (s, 3H), 4.18 (q, 2H), 4.22-4.33 (m, 2H), 6.41 (s, 1H), 8.22 (s, 1H). Exact mass calculated for C17H19BrF3N5O3 477.06, found 478.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NCCCO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCO)cn1
Yield: 84 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-amino-1-propanol instead of 2-aminoethyl isopropylether, to the title compound (200 mg, 84%) which was obtained as a colourless oil. MS: m/e=368.0 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][C@@H:7]1[CH2:11][C@@H:10](O)[C@@H:9]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1C=CC=C[CH:30]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([Si:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:30]#[N:29])[C@@H:9]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccncc1
Reactant: CC(C)O[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)O[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1C#N
Temperature: -35 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
(1S,2R,4S) and (1R,2S,4R)-4-(tert-Butyl-diphenyl-silanyloxy)-2-isopropoxy-cyclopentanol (510 mg, 1.28 mmol) was dissolved in DCM (12 ml) and pyridine was added (206 μl, 2.56 mmol). The mixture was cooled to −35° C. and a solution of trifluoromethanesulfonic anhydride (253 μl, 1.54 mmol) in DCM (3 ml) was added. After the reaction mixture had been stirred for 5 h at −20° C. it was concentrated and passed trough a short plug of silica gel and then evaporated to dryness. The remaining oil was dissolved in THF (12 ml) and a solution of tertrabutylammonium cyanide in THF (3 ml) was added dropwise at −45° C. The reaction mixture was stirred at room temperature over night and then evaporated. The remaining yellow oil was purified by silica column chromatography (heptane/EtOAc 9:1) to obtain the title compound (311 mg, 60%) as colorless oil. MS (EI): 408.4 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].CO>C1COCC1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH:20]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(c1ccc(OC2CCC(c3ccccc3)CC2)cc1)c1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC(c1ccc(OC2CCC(c3ccccc3)CC2)cc1)c1cccs1

Procedure:
Compound 30 (0.048 g, 0.11 mmol) was added to a 1-dram vial and dissolved in a minimal amount of anhydrous THF. An aqueous solution of lithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was added dropwise until the layers were miscible. The vial was sealed and placed on a rotating wheel overnight (18 hours). When the reaction was complete, the solvent was concentrated under a flow of nitrogen until only water was left. The mixture was diluted by the addition of ˜1 mL of water. Hydrochloric acid (3 N aqueous solution) was added dropwise until the pH reached 2. The aqueous solution was extracted with DCM, and the organic layer was dried and concentrated. Flash column chromatography with 0 to 100% EtOAc/hexanes as the eluant and HPLC of the residue afforded 31 as a white film. MS ESI (pos.) m/e: 407.2 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.35-7.2 (m, 7H); 7.17 (dd, J=5.1, 1.0 Hz, 1H); 6.93-6.73 (m, 4H); 4.72 (m, 1H); 4.61 (m, 1H); 3.16 (dd, J=15.9, 7.6 Hz, 1H); 3.07 (dd, J=15.9, 7.9); 2.61 (m, 1H); 2.19 (m, 2H); 2.02-1.95 (m, 2H); 1.73-1.61 (m, 4H); 0.91-0.69 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].[OH-].[K+].O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:19][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Temperature: 150 °C
Yield: 54.8 %

Procedure:
5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (500.0 mg, 0.00315 mol), 3,4-dichlorophenol (565 mg, 0.00344 mol) and potassium hydroxide (265 mg, 0.00472 mol) were stirred in DMF (2.0 mL). Mixture was heated at 150° C. for 20 min using microwave. Water was added and resulting mixture was extracted with ethyl acetate. Organic layer was washed with brine twice, dried over MgSO4 and evaporated. The resulting oil was purified by column chromatography (10% to 20% ethyl acetate/heptane) to give 5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (492 mg, 54.7%) as white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)cc1

Procedure:
104 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(4-methoxyphenyl)piperazine (53 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[CH:9]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([C:16]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: COC(=O)C(C)N
Agent: Cl
Product: CC(NC(=O)C1CCCCCC1)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of example 4A using 20 g (143 mmol) of D,L-alanine methyl ester hydrochloride and 23.02 g (143 mmmol) of cycloheptanoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[Br:14][CH2:15][C:16](Cl)=[O:17]>C(N(CC)CC)C>[Br:14][CH2:15][C:16]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)=[O:17]
Reactant: COc1ccc2c(c1)CNCCS2
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)CBr)CCS2
Yield: 51.5 %

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.0 g), triethylamine (3.1 g) and bromoacetyl chloride (3.2 g) were reacted in the same manner as in Experimental Example 1 to give 4-bromoacetyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.5 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:28])=[CH:22][CH:21]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(Cc4ccccc4)C[C@@H]3C(C)C)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 64 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg, 0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazine followed by the addition of triethylamine (206 μL). The reaction was heated at 85° C. for two hours. The reaction was quenched with water after cooling it to room temperature. The aqueous layer was extracted twice with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and concentrated. The reaction was purified via silica gel chromatography using 1:1 hexanes:CH2Cl2 solvent system to yield 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (230 mg, 64%). LC/MS: m/z 453.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([N:1]3[C:20](=[O:21])[C:19]4[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=4[C:17]3=[O:22])=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reactant: O=C1OC(=O)C2=C1CCCC2
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(OCc2ccc(Cl)cc2)cn1

Procedure:
The compound, 2-amino-5-(4-chlorobenzyloxy)pyridine is reacted with 3,4,5,6-tetrahydrophthalic anhydride using the procedure of Example 1 to yield N-[5-(4-chlorobenzyloxy)-2-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:10][C:9]2[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:20][C:21]#[N:22]>CN(C)C=O.O>[C:21]([CH2:20][N:8]1[C:9]2[CH2:10][C:2]([F:1])([F:16])[CH2:3][CH2:4][C:5]=2[CH:6]=[C:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:22]
Reactant: CCOC(=O)c1cc2c([nH]1)CC(F)(F)CC2
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(n1CC#N)CC(F)(F)CC2
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 113l (5.0 g, 21.81 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), followed by the addition of sodium hydride (1.3 g, 54.17 mmol, 1.40 equiv, 60%) in several batches at 0° C. over 10 min. (FIG. 14). To this was added 2-bromoacetonitrile (3.7 g, 30.85 mmol, 1.40 equiv) dropwise with stirring at 20° C. over 10 min. The resulting solution was stirred at room temperature for 7 h, diluted with 100 mL of water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to afford 3.3 g (56%) of 113m as a light yellow oil.