Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.C([O-])(=O)C.[K+].B(O)O>O1CCOCC1>[C:10]([NH:9][CH2:8][C:5]1[N:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(=O)NCc1ccc(Br)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: OBO
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)C(=O)NCc1ccc(B(O)O)cn1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture N-((5-bromopyridin-2-yl)methyl)isobutyramide (228 mg, 0.887 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (293 mg, 1.153 mmol), PdCl2(dppf)-CH2Cl2Adduct (72.4 mg, 0.089 mmol) and potassium acetate (218 mg, 2.217 mmol) in Dioxane (6 mL) was heated to 70° C. for 3 hr. LCMS indicated that the major product was boronic acid. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was concentrated to afford (6-(isobutyramidomethyl)pyridin-3-yl)boronic acid (195 mg, 0.878 mmol, 99% yield) as a brown oil. The material was used as is in the next step. The yield is assumed to be quantitative. MS (ES+) m/z: 223.1 (M+H); LC retention time: 0.43 min (analytical LCMS Method B).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)=[C:27]([Cl:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([Cl:38])[C:28]([O:32][CH2:33][CH:34]5[CH2:37][CH2:36][CH2:35]5)=[C:29]([Cl:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2cc(Cl)c(OCC3CCC3)c(Cl)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCC4CCC4)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (45 mg, 0.251 mmol) with 2-bromo-N-{4-[4-(cyclobutylmethoxy)-3,5-dichlorophenyl]-1,3-thiazol-2-yl}acetamide (135 mg, 0.301 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 65 mg of the product as an off-white solid; 1H NMR ((δ ppm, 300 MHz, DMSO-d6) 1.90-1.99 (m, 4H), 2.04-2.10 (m, 2H), 2.72-2.80 (m, 1H), 3.17 (s, 3H), 3.39 (s, 3H), 4.00 (d, J=6.3 Hz, 2H), 5.32 (s, 2H), 6.22 (s, 1H), 7.36 (s, 1H), 7.85 (s, 1H), 8.00 (s, 2H), 12.68 (br s, 1H); ESI-MS (m/z) 548.15 (M+H)+.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH:5](O)[CH3:6])[CH3:3].[CH2:9]([C:12]1[C:18]([OH:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:13]=1[OH:14])[CH2:10][CH3:11].C(OC(C)C)(C)C.S(=O)(=O)(O)O>>[OH:19][C:18]1[C:12]([CH2:9][CH2:10][CH3:11])=[C:13]2[C:15]([CH:5]([CH3:6])[CH2:4][C:2]([CH3:3])([CH3:1])[O:14]2)=[C:16]([CH3:20])[CH:17]=1
Reactant: CCCc1c(O)cc(C)cc1O
Reactant: CC(O)CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: CCCc1c(O)cc(C)c2c1OC(C)(C)CC2C
Yield: 72.6 %

Procedure:
An amount of 1.77 g. of 2-methylpentane-2,4-diol were added dropwise at the temperature of approximately 60° C. to a mixed solution prepared from 2.49 g. of 2-propyl-5-methyl resorcinol, 15 ml of isopropyl ether and 1 ml of concentrated sulfuric acid. The solution was cooled, and successively washed with water, aqueous 1 N sodium hydroxide solution, and again with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to column chromatography filled with silica gel. There were thus obtained 2.7 g. (yield: 72.6%) of the subject compound in oily form.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]2)=[O:9])[CH:2]=1.I[Si](C)(C)C>ClCCl>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)N1CCN(C(=O)Nc2cccc(C)c2)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A suspension of ethyl 4-(m-tolylcarbamoyl)piperazine-1-carboxylate (example 59, 1.5 g, 5.15 mmol) in dichloromethane (25 ml) was treated dropwise at room temperature with iodotrimethylsilane (1.6 ml, 11.3 mmol). The reaction mixture was stirred under nitrogen at room temperature overnight. The volatiles were evaporated to dryness, diluted with methanol and the solid was filtered off. The solid was washed with methanol and dichloromethane and dried under vacuum to yield the title compound as a yellow solid (1.1 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1>CC(C)=O.O=[Mn]=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2cc(CO)ccc2O)cc1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(C=O)ccc2O)cc1
Reaction time: 72 h
Yield: 108.8 %

Procedure:
A solution of 4-hydroxy-3-(4-methoxyphenyl)benzyl alcohol (5.54 g, 24 mmol) in acetone (250 mL) was treated with MnO2 and the mixture stirred for 3 days. The solid was filtered on diatomaceous earth and the filtrate was concentrated under reduced pressure to afford 5.96 g of title compound as a pale green oil, impure with manganese salts.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[N:17]1[C:22]2[N:23]=[C:24]([NH:35][CH2:36][C:37](OC)=[O:38])[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C:21]=2[CH:20]=[CH:19][C:18]1=[O:41]>>[CH:1]1([NH:4][C:37](=[O:38])[CH2:36][NH:35][C:24]2[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C:21]3[CH:20]=[CH:19][C:18](=[O:41])[N:17]([C:11]4[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=4[F:9])[C:22]=3[N:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NC1CC1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)NC2CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the procedure outlined in Example 193, cyclopropylamine (0.23 mL, 3.3 mmol), trimethylaluminum (1.7 mL, 3.3 mmol) and the product of Example 190 (150 mg, 0.33 mmol) were reacted to give the desired product, 20 mg (13%). LC-MS: 480.0 (MH+, m/z), 1.89 (Rt, min).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[C:18]([Br:24])[CH:19]=[C:20]([I:23])[CH:21]=2)[C:16]([OH:35])([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:15]1=[O:36])(C(C)(C)C)(C)C.OS([O-])(=O)=O.[K+]>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[C:18]([Br:24])[CH:19]=[C:20]([I:23])[CH:21]=2)[C:16]([OH:35])([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:15]1=[O:36]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Br)cc(I)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N(CCCCCO)c2cc(I)cc(Br)c2C1(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 1-(5-t-butyldimethylsilyloxypentyl)-4-bromo-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole (450 mg, 0.67 mmol) in THF (5 mL) was added 1 N n-tetrabutylammonium fluoride in THF (1 mL, 1 mmol) and the mixture was stirred for 4 h at room temperature. 5% KHSO4 was added and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 1:1 to 0:1 hexane/ethyl acetate to give the title compound (349 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:19][CH2:18][CH2:17][CH:10]1[C:9](=[O:12])[NH:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (800 mg, 4.5 mmol) in DMF (16 mL) was added sodium hydride (60% in mineral oil, 260 mg, 6.5 mmol). After 20 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.5 mmol) was added and it was heated to 70° C. in the microwave for 40 minutes. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (4×50 mL). The combined organic phases were washed with water (6×250 mL), dried over magnesium sulfate and concentrated at reduced pressure to afford the product as a yellow oil which was used without further purification. (1.38 g, 91%).
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2(OC)C=CC=CC2)=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[N:18][C:19]=2[NH:48][O:49][CH3:50])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C(#N)C.O>[CH:8]([O:7][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][OH:26])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:51]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)=[N:18][C:19]=2[NH:48][O:49][CH3:50])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:9])[CH3:10]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCOC(c1ccccc1)(c1ccccc1)C1(OC)C=CC=CC1)n2COCP(=O)(OC(C)C)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCO)n2COCP(=O)(OC(C)C)OC(C)C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
A solution of 35 (52.2 g, 55.18 mmol) in acetonitrile (2 L) is treated with conc. HCl (4 mL) at room temperature and the mixture is stirred for 24 h. The reaction is neutralized with 2N NaOH and diluted with water (250 mL). It is then concentrated to remove most of acetonitrile and treated with ethyl acetate (500 mL) and water (200 mL). The organic layer is separated and dried over MgSO4. After filtration, the filtrate is concentrated and the residue is purified on a silica gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.2) as eluent to give 6.18 g (17%) of 36 as a white solid: 1H NMR (DMSO-d6): δ 8.27 (s, 1H), 7.93 (s, 1H), 7.38-7.20 (m, 13H), 6.89 (d, J=9.0 Hz, 2H), 4.92-4.80 (m, 1H), 4.64 (t, J=5.1 Hz, 1H), 4.50-4.36 (m, 2H), 4.14 (t, J=9.8 Hz, 1H), 3.89-3.65 (m, 3H), 3.76 (s, 3H), 3.42-3.18 (m, 2H), 2.22-1.95 (m, 2H), 1.18-1.11 (m, 6H), 1.06 (d, J=6.2 Hz, 6H). IR (KBr, cm−1) 3418, 2978, 1605, 1503 and 1250. Anal. Calcd for C36H44N5O6P.0.5 H2O: C, 63.33; H, 6.64; N, 10.26. Found: C, 63.31; H, 6.47; N, 10.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](C)[N:20]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].NC1N=CN=C(C[OH:37])C=1.ClC1C=C(C=C(Cl)C=1N1C=C2C(Cl)=NC=CC2=N1)C#N>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18][C:19]3[CH:24]=[C:23]([CH2:25][OH:37])[N:22]=[CH:21][N:20]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6]
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)nc(C)n1
Reactant: Nc1cc(CO)ncn1
Agent: N#Cc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Product: N#Cc1cc(Cl)c(-n2cc3c(Nc4cc(CO)ncn4)nccc3n2)c(Cl)c1
Yield: 37 %

Procedure:
Following the procedure described for 3,5-dichloro-4-[4-(2,6-dimethylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile, (6-amino-pyrimidin-4-yl)-methanol and 3,5-dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile were reacted to afford the title compound as a pale yellow solid (70 mg, 37% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.22 (s, 1H), 8.70 (s, 2H), 8.49 (s, 2H), 8.00 (d, J=6.4 Hz, 1H), 7.25-7.22 (m, 1H), 5.61 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.8 Hz, 2H). LCMS (Method D): RT=2.05 min, m/z: 412 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.ClC1C=C[C:21]([C:24]2[O:28][N:27]=[C:26]([C:29](O)=O)[C:25]=2C)=CC=1>>[Cl:1][C:2]1[C:3]([C:14]([NH:27][C@@H:26]2[CH2:29][CH2:21][C@H:24]([OH:28])[CH2:25]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Reactant: Cc1c(C(=O)O)noc1-c1ccc(Cl)cc1
Product: O=C(N[C@@H]1CC[C@H](O)C1)c1noc(-c2ccc(Cl)cc2)c1Cl

Procedure:
Using 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid, synthesised according to Example 1, in place of 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)/[CH:8]=[C:9]1/[C:10](=[O:29])[N:11]2[C@@H:16]([CH2:17][CH2:18]/1)[CH2:15][CH2:14][CH2:13][C@H:12]2[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1.Cl>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)/[CH:8]=[C:9]1/[C:10](=[O:29])[N:11]2[C@@H:16]([CH2:17][CH2:18]/1)[CH2:15][CH2:14][CH2:13][C@H:12]2[C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc([C@@H]2CCC[C@@H]3CC/C(=C\c4ccc(-n5cnc(C)c5)c(OC)c4)C(=O)N32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(C(=O)O)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A 2 N sodium hydroxide solution (1 mL) was added to a solution of methyl (E)-4-{(4S*,9aR*)-7-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-oxooctahydroquinolizin-4-yl}benzoate (80 mg) in methanol (2 mL), and the reaction solution was stirred at room temperature for 18 hours. 2 N hydrochloric acid (1 mL) was added to the reaction solution, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol=5:1) to obtain 77 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](Br)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27]>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]4)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: CC(C)N1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: CC(C)N1CCN(c2nnc3n2-c2ccc(C(F)(F)F)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 8-(trifluoromethyl)-1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-isopropylpiperazine to give 8-(trifluoromethyl)-1-(4-isopropylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:24]([OH:26])=[O:25])[CH2:7]2)[CH3:2].Cl.CC(O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH2:10][NH:9][C@H:8]([C:24]([OH:26])=[O:25])[CH2:7]2)[CH3:2]
Reactant: CCOc1cc2c(cc1OCC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOc1cc2c(cc1OCC)C[C@@H](C(=O)O)NC2
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (S)-1,2,3,4-tetrahydro-6,7-diethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid (example 4) (18.3 g, 0.05 mol), 20% HCl/IPA solution (18.3 g, 0.1 mol) in ethyl acetate (100 mL) was stirred at 40° C. for 3 hrs. The resulting suspension was cooled to room temperature, filtered, and rinsed with ethyl acetate (2×30 mL). The solids were dried under vacuum to give 12.1 g of (S)-1,2,3,4-tetrahydro-6,7-diethoxy-3-isoquinolinecarboxylic acid. Yield 81%. 1H NMR (DMSO-d6) δ: 1.32 (t, J=6.9 Hz, 6H, CH2CH3), 3.03 (dd, J=16.7, 10.9 Hz, 1H, CHHCHCOOH), 3.21 (dd, J=16.7, 4.9 Hz, 1H, CHHCHCOOH), 3.9-4.06 (m, 2H, CH2CH3), 4.2 (br s, 2H, CH2N), 4.33 (dd, J=10.9, 4.9 Hz, 1H, CHCOOH), 6.84, 6.85 (s, 2H, PhH), 9.96 (br s, 2H, NHHCl).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21]([N:23]2C=CN=C2)=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1.N.O1CCOCC1>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21]([NH2:23])=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nc(NC(N)=O)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, prepared as in Step III of Example 36, described above (535 mg; 1.33 mmol) is added DMF (20 ml) and ammonia 0.5 M solution in dioxane (3.20 ml; 0.50 M; 1.60 mmol; 1.10 eq.). The mixture is stirred at rt overnight. Some ammonia 0.5 M solution in dioxane (1.46 ml; 0.50 M; 0.73 mmol; 0.50 eq.) is added and the mixture is stirred at rt for 5 additional hours. As the reaction is complete, solvents are evaporated. The resulting crude yellow product is purified by preparative HPLC, affording Compound (40) as white-off powder (177 mg; 26%). 1H NMR (DMSO-d6, 300 MHz) δ 2.41 (s, 3H), 3.68 (m, 6H), 4.32 (m, 2H), 6.42 (br s, 2H), 7.91 (s, 1H), 10.45 (br s, 1H). M− (ESI): 352.12; M+ (ESI): 354.11. HPLC (method A), Rt: 2.03 min (purity: 99.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:31].[CH:32](O)([CH3:34])[CH3:33]>>[ClH:31].[ClH:31].[CH:32]([O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)([CH3:34])[CH3:33]
Reactant: O=C(O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 75.85 %

Procedure:
To a stirred solution of {4-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-yl}-(Z)-but-2-enyloxy}acetic acid (1.0 g, 0.0024 mol) in isopropyl alcohol (20 ml), is added a solution of anhydrous HCl in isopropyl alcohol till pH of solution is 1-2. The solution is refluxed for around 2 hrs, cooled to 25-30° C. and stirred for 4 hrs. The crystallized solid is filtered, washed with isopropyl alcohol (2×5 ml), and dried in oven at 60-65° C. to get product 0.968 g (75.85% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:20]=[O:21])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])=[O:11])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:20][OH:21])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])=[O:11])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1sc(C=O)c(C)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN1CCCC1CNC(=O)c1sc(CO)c(C)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±) N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-formyl-3-methoxy-4-methylthiophene-2-carboxamide (1.15 g) in ethanol (30 ml) was added sodium borohydride (0.154 g) in one portion. The solution was stirred at room temperature for 2 hours and then water (50 ml) added. After extraction with ethyl acetate, washing the organic extracts with water, drying over magnesium sulphate and filtering, the solvent was removed in vacuo to give the title compound as a golden oil, fumarate salt, m.p. 118°-119° C. (ex ethylacetate-ethanol ether as recrystallising solvent).
Reaction SMILES: [S:1]([O:5][C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])([OH:4])(=[O:3])=O.[F:13][C:14]1[C:15]2[CH2:16][CH:17]3[CH:26]([NH2:27])[CH:20]([CH2:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)[CH2:19][CH2:18]3>C1COCC1.C(OCC)(=O)C>[OH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[O:5][S:1](=[O:3])(=[O:4])[NH:27][CH:26]1[CH:20]2[CH2:19][CH2:18][CH:17]1[CH2:16][C:15]1[C:14]([F:13])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:21]2
Reactant: NC1C2CCC1Cc1c(F)cccc1C2
Reactant: O=S(=O)(O)Oc1ccccc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(NC1C2CCC1Cc1c(F)cccc1C2)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
Catechol sulphate (332 mg, 1.93 mmol) was added to an ice-cooled solution of the amine from Step 4 (360 mg, 1.76 mmol) in THF (5 ml). The mixture was allowed to warm to room temperature, stirred for 18 hours, diluted with ethyl acetate and washed with ammonium chloride (aq) followed by brine. The organic phase was dried and evaporated to give a crude oil which was purified by column chromatography on silica gel eluting with 4:1 isohexane-ethyl acetate to give an orange oil 335 mg (51%). 1H NMR (CDCl3, 360 MHz) δ 7.27 (1H, m), 7.21 (1H, m), 7.05 (2H, m), 6.85–7.95 (3H, m), 6.32 (1H, br s), 5.40 (1H, br d, J=7.5 Hz), 4.02 (1H, q, J=6.4 Hz), 3.19–3.25 (1H, dd, J=16.7, 7.6 Hz), 3.04 (1H, d, J=16.3 Hz), 2.70 (1H, m), 2.50–2.61 (3H, m), 1.74 (2H, m), 1.21 (2H, m). m/z 376 (M−H)−
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH:24]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>>[C:30]1([C:28]2[N:29]=[C:25]([CH:24]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][NH:15]3)[NH:26][CH:27]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Temperature: 25 °C

Procedure:
Triflouroacetic acid (TFA) (4 mL) was cooled in a test tube to about 0° C. To the cool solvent was then added the product prepared in Step B (0.75 g, 2 mmol) above. The reaction mixture was allowed to warm to room temperature over about 45 minutes. Excess TFA was removed under a stream of N2 gas. The residue was partitioned between dichloromethane (15 mL) and saturated NaHCO3. The aqueous phase was then re-extracted with a second portion of dichloromethane and the organic phases combined, dried over MgSO4 and filtered, to yield the title compound in dichloromethane solution. The filtrate was used in the next step without further purification or isolation.