Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]([CH3:26])[CH2:16][CH:17]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[CH:17]([CH2:16][CH:15]([CH3:26])[CH3:14])[CH3:18])=[O:12]
Reactant: CC(C)CC(C)c1ccccc1N
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CC(C)c1ccccc1NC(=O)c1c(C(F)F)nn(C)c1Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
0.458 g (2.00 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is added to a mixture of 0.322 g (1.81 mmol) of 2-(4-methylpentan-2-yl)aniline and 0.377 g (2.72 mmol) of potassium carbonate in 30 mL of acetonitrile, and the mixture is stirred at 20° C. overnight. After the reaction has ended, the mixture is extracted with water/ethyl acetate. The organic phase is dried with sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate gradient). This gives 0.580 g (78% of theory) of 5-chloro-3-(difluoromethyl)-1-methyl-N-[2-(4-methylpentan-2-yl)phenyl]-1H-pyrazole-4-carboxamide having a content of 94% according to LC-MS and a logP (acidic) of 4.01.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]3)=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCOC(=O)C1=Cc2cc(O)ccc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OCC(=O)c3ccc(Br)cc3)ccc2OC1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
The mixture of ethyl 6-hydroxyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.0 g, 3.47 mmol), 2-(4-bromophenyl)-2-oxoethyl bromide (0.96g, 3.47mmol) and potassium carbonate (0.96 g, 6.94 mmol) in 4 mL of dry DMF was heated to 70° C. and shaken for two hrs, then at room temperature overnight. The solid was filtered, and washed with ethyl acetate. The combined organic phases were washed with brine, and then dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane. It gave 0.65 g of light yellow solid (38.6%). M.P.=130.5-131.5° C. 1HNMR (CDCl3/400 MHz) 7.86(m, 1H), 7.83(m, 1H) 7.65(m, 1H), 7.63-7.62(m, 2H), 6.89-6.88(m, 2H), 6.77(m, 1H),5.64(q, J=6.8 Hz, 1H, ), 5.16(s, 2H), 4.33-4.26(m, 2H), 1.33(t, J=7.2 Hz, 3H). 13C NMR (CDCl3/300 MHz), 193.8, 163.9, 153.3, 148.2, 136.8, 133.3, 132.5, 129.9, 129.5, 123.6 (q, J=287.9 Hz), 119.9, 119.8, 117.8, 117.1, 115.1, 71.8, 70.8(q, J=32.8 Hz), 61.7, 14.4. 19F(CDCl3/400 MHz) −78.72(d, J=6.8 Hz). LC-MS: 484.9 (M+1, 100), 486.9(M+3, 100). Purity =95%. HRMS (ES+) m/z calcd for (C21H16BrF3O5) 502.0471(M+NH4), 504.0454 (M+NH4+2), found 502.0484, 504.0492.
Reaction SMILES: [CH3:1][C:2]1[C:9]2[CH2:8][O:7][C:6](=[O:10])[C:5]=2[S:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.ClCCl>[Br:11][C:3]1[S:4][C:5]2[C:6](=[O:10])[O:7][CH2:8][C:9]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1csc2c1COC2=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)sc2c1COC2=O

Procedure:
In a 50 mL round bottom flask was added 3-methylthieno[2,3-c]furan-6-(4H)-one (130 mg, 0.843 mmol, 1.0 eq) and chloroform (5 mL). To above solution was added bromine (86 μL, 1.08 mmol, 2.0 eq) in chloroform. The reaction was heat to reflux for 3 hr, cooled down, diluted with dichloromethane, washed with water, diluted sodium thiosulfate. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 235.2 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 5.16 (2H, s), 2.19 (3H, s);
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12]/[C:13]/2=[N:16]/[OH:17])=[CH:9][CH:8]=1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>C(Cl)Cl>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:17]/[N:16]=[C:13]1/[CH2:12][CH2:11][C:10]2[C:14]/1=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=2)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O/N=C1/CCc2ccc(Br)cc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](O/N=C1/CCc2ccc(Br)cc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of imidazole (11 g, 162 mmol) in 100 mL of dry DCM was added dropwise to a solution of (Z)-6-bromo-2,3-dihydro-1H-inden-1-one oxime (1C) (18.2 g, 81 mmol) and triisopropylsilyl chloride (23.3 g, 121.5 mmol) in solution in 40 mL of dry DCM. The reaction mixture was stirred for 16 hours at rt. It was then filtered to remove the precipitate and the filtrate was concentrated under vacuum. The crude material was purified by column chromatography on silica gel to provide (Z)-6-bromo-2,3-dihydro-1H-inden-1-one O-triisopropylsilyl oxime (10). The crude product was taken on to the next step immediately.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: C1CCNCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 20.4 mg (0.24 mmol) piperidine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 33 mg (53.3%) product as an orange powder. MS (ESI) m/z 516.25 (M+1).
Reaction SMILES: [P:1]([O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[F:50])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:51][CH3:52])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[P:1]([OH:3])([OH:8])([O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[F:50])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:51][CH3:52])=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4ccccc4F)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4ccccc4F)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(O)O
Yield: 100.6 %

Procedure:
An analogous reaction to that described in example 28 but starting with di(tert-butyl) ((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (612 mg, 0.81 mmol) yielded the title compound (527 mg, 86% yield) as a yellow dihydrochloride salt:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccn1
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1NCc1ccccn1

Procedure:
10 g of N-2-picolyl-o-nitroaniline are hydrogenated with Raney nickel in methanol at room temperature to give the o-phenylenediamine derivative which remains as an oil, after the catalyst has been filtered off and the solvent has been evaporated in vacuo.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45]([N:47]1C=C(C2C=CC=C(N)C=2)N=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:46])[N:47]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:48])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)OC(=O)n1cnc(-c2cccc(N)c2)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 4-(3-amino-phenyl)-imidazole-1-carboxylic acid tert-butyl ester (prepared in three steps from 2-bromo-3′-nitroacetophenone) was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.35 (1H, s), 7.82 (1H, s), 7.68 (1H, s), 7.51-7.46 (3H, m), 7.33-7.19 (5H, m), 7.04 (1H, d, 8.1), 4.78 (1H, d, 17.1), 4.66 (1H, d, 17.1), 4.35 (1H, d, 16.5), 4.22 (1H, d, 16.5), 2.80 (1H, m), 2.05-1.62 (5H, m), 1.31-1.18 (14H, m). Found C, 62.46; H, 7.01; N, 14.35%; C31H36N6O3.3.0H2O requires C, 62.61; H, 7.12; N, 14.13%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])O[C:6]2=[O:11].Cl.[NH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:11]
Reactant: COC(=O)CN
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: Cl
Product: COC(=O)CN1C(=O)c2cccc(O)c2C1=O
Yield: 18.6 %

Procedure:
4-Hydroxyisobenzofuran-1,3-dione (600 mg, 3.66 mmol) and methyl 2-aminoacetate hydrochloride (505 mg, 4.02 mmol) were finely dispersed on Montmorillonite K10 (powder, Sigma-Aldrich) (1.2 g) and the solid mixture was reacted under microwave irradiation at 150° C. for 30 minutes. Montmorillonite was washed with MeOH and the solvent was evaporated under vacuum. The crude was purified by preparative HPLC (Method 1) recovering the title compound (160 mg, 0.680 mmol, 19% yield). MS/ESI+ 236.1 [MH]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:14]2[S:18][C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)=[N:16][C:15]=2[CH3:25])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]>C(Cl)(Cl)Cl.CO>[Br:1][C:24]1[C:20]([NH:19][C:17]2[S:18][C:14]([C:6]3[CH:7]=[CH:8][C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:4]([F:3])[CH:5]=3)=[C:15]([CH3:25])[N:16]=2)=[N:21][NH:22][CH:23]=1
Reactant: Cc1nc(Nc2cc[nH]n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(Nc2n[nH]cc2Br)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
Bromine (0.012 ml, 0.23 mmol) in chloroform (0.5 ml) is added dropwise to a stirred solution of [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine (69) (0.10 g, 0.23 mmol) in chloroform (1 ml) and methanol (2 ml). After stirring at room temperature for 1 hour the hydrobromide salt of the titled compound precipitates. This is removed by filtration and washed with ether.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][NH:26][CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1([CH2:42][C:43](O)=[O:44])[CH:41]=[N:40][CH:39]=[N:38]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:43](=[O:44])[CH2:42][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cncn1
Reactant: CCC(CC)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Product: CCC(CC)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1cncn1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methylvalerohydrazide and using 1,2,4-triazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methyl-2′-[2-(1H-1,2,4-triazol-1-yl)acetyl]valerohydrazide.
Reaction SMILES: CC([N:5]([C@@H:9]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([O:30][CH3:31])[CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:5])=[CH:17][CH:18]=2)=[CH:24][C:25]=1[O:30][CH3:31]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C(C)C)N(C(=O)[O-])C(C)(C)C)cc2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)C)cc2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-2-methyl-1-{[(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)amino]carbonyl}propyl)carbamate (Intermediate 82, 110 mg) in dry dichloromethane (3 mL), TFA (1 mL, 12.98 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a yellow pale solid (68 mg).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)=[N:4][CH:3]=1.O.NN>C1COCC1.[Ni]>[S:6]1[CH:2]=[CH:3][N:4]=[C:5]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncc(Cl)s2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2nccs2)c1
Yield: 86.4 %

Procedure:
To a solution of 5-chloro-2-(3-nitro-phenyl)-thiazole (20.0 g, 69.6 mmol) in THF (260 ml) was added hydrazine monohydrate (13.5 ml, 278 mmol) and Raney nickel (2 g). The resultant mixture was stirred at ambient conditions for 1 hour and then filtered through celite. The filtrate was evaporated to dryness and the filtrate was partitioned between ethyl acetate and saturated, aqueous sodium carbonate. The organic layer was dried over sodium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with a mixture of ethyl acetate and ligroin (1:3 v/v) to afford the desired product (10.6 g, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+].C(O)(=O)C(O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(COc2ccc3[nH]cc(CCNCc4cccc(Oc5ccccc5)c4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 5-benzyloxy tryptamine (1.23 g, 4.6 mmol), 3-phenoxybenzaldehyde (97%, 1.09 g, 5.53 mmol) and molecular sieves 4 A (1.0 g) and stir in methanol (15 mL) for 4 h. Filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaBH4 (174 mg, 4.60 mmol), stir the resulting mixture at room temperature for 1 h. Remove MeOH under vacuum, dilute the residue with CH2CL2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate the solvent in vacuo. Purification by silica gel chromatography(CH2Cl2/MeOH) to give the free base. Combine the free base with oxalic acid to form the salt: (300 MHz, DMSO-d6) 2.95–3.15 (m, 4H), 3.93 (s, 2H), 4.10 (br, 1H), 5.05 (s, 2H), 6.85–7.46 (m, 18H), 10.67 (br, 1H); ms (ELECTROSPRAY) m/e: 449.2 (M+1).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([C:10]([O:12]C)=[O:11])[C@H:7]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C@@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:4].[OH-].[Li+].O.Cl>CO>[C:23]([O:22][C:20]([NH:19][C@H:6]1[C@@H:7]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:10]([OH:12])=[O:11])[CH2:9][C@@H:5]1[C:3]([OH:4])=[O:2])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)[C@H](CNC(C)=O)[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@@H](C(=O)O)C[C@H]1C(=O)O

Procedure:
(±)-(1S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (255 mg, 0.68 mmole) and lithium hydroxide (2.2 equivalents) in 15 mL of 4:1 methanol:water were reacted at room temperature for 2 hours. The reaction was acidified with dilute HCl and extracted with ethyl acetate (3×60 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:9][CH2:10][C:11]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8])=[O:12]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)c1cc(Cl)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(Ref: J. Org. Chem. 1955; 20; 813-818) A mixture of 4-chlorophenol (5 g; 39.0 mmol) and chloroacetyl chloride (3.41 mL; 42.8 mmol) was heated to 80° C. for 2.5 hours. Mixture cooled to 30° C. and aluminum chloride (5.2 g; 39.0 mmol) was added over 30 minutes. Mixture heated to 130° C. for 15 hours. Mixture cooled under N2 flow and reaction was quenched with 0.5 g of ice chuncks over 5 minutes. Mixture was treated with 12 mLs of 20% HCl and heated to 60° C. for 15 minutes (fumes generated). Mixture cooled back room temperature and after 30 minutes 2 phases observed. Aqueous phase was extracted, and oil organic layer was triturated with petroleum ether. Petroleum ether was decanted off. Mixture was then heated to 60° C. in 100 mL of benzene and charcoal. Mixture filtered and filtrate was concentrated to a third volume. Another 40 mLs of petroleum ether added and allowed to stand overnight. Mixture was decanted and mother liquor was evaporated to afford 2-chloro-1-(5-chloro-2-hydroxy-phenyl)-ethanone. (5 g; 63% yield).
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][C:6]12OC(=O)C(=O)[N:7]1[CH2:8][CH2:9][C:10]1[C:15]2=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1.C[CH2:24][O:25]C(C)=O.O>CO>[CH2:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][O:25][CH3:24])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCOC(C)=O
Reactant: CCc1ccc2c(c1)C1(CCl)OC(=O)C(=O)N1CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1ccc2c(c1)C(COC)=NCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium methoxide (9.46 g) was added to a suspension of 10b-(chloromethyl)-9-ethyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (14.0 mL) in MeOH (140 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hours and then heated under reflux for 3 hours. EtOAc and water were added to the mixture, followed by filtration. The organic layer of the filtrate was collected, washed with saturated brine, and dried over magnesium sulfate. Activated carbon and silica gel were added thereto, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4.75 g).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:23]1[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:26]1[CH:25]=[CH:24][C:23]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:31][CH:30]=1)[CH3:4])#[N:2]
Reactant: CCCCCCCCCCc1ccc(C(=O)O)cc1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCCCCCc1ccc(C(=O)N[C@@H](C)C#N)cc1

Procedure:
General procedure D was used to deprotect 0.198 g (1.2 mmols) of 4. The product was immediately carried on using general procedure F and coupled to 1.2 mmols of 7. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (1:3) to yield 0.2 g (0.63 mmols). 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J=8.2, 2H), 6.94 (d, J=7.3, 1H), 5.19-5.11 (m, 1H), 2.66-2.60 (m, 2H), 1.64 (dd, J=2.0, 7.2, 2H), 1.59 (dd, J=5.9, 13.3, 2H), 1.30 (dd, J=18.9, 22.5, 13H), 0.88 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 173.67, 166.98, 147.92, 147.35, 129.98, 128.73, 127.28, 119.51, 52.38, 48.45, 36.25, 35.86, 31.88, 31.16, 29.59, 29.56, 29.45, 29.31, 29.23, 22.67, 19.47, 18.62, 14.12.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:17][N:18]1C(=O)C2C(=CC=CC=2)C1=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CCO>[CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: CCO
Product: NOC(C(=O)OCc1ccccc1)c1ccccc1
Yield: 95.2 %

Procedure:
A solution of the compound from Step 4a (3.8 g, 9.8 mmol) and hydrazine (0.64 mL, 20 mmol) in EtOH (30 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and solvent was reduced under reduced pressure giving 2.4 g (95%) of the title compound, which was used without additional purification.