Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH3:30])[C:23]([CH:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[C:34]1[N:38]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[CH:43]=[CH:42]3)[C:37](=[O:49])[NH:36][N:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.Cl>ClCCl.CO>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH3:30])[C:23]([CH:31]([CH3:32])[CH3:33])=[CH:22][C:21]=1[C:34]1[N:38]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[CH:43]=[CH:42]3)[C:37](=[O:49])[N:36]([C:9]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:10])[N:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOCOc1cc(OCc2ccccc2)c(-c2n[nH]c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOc1cc(OCc2ccccc2)c(-c2nn(C(=O)OCc3ccccc3)c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cbz-Cl was added to the solution of 3-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-1H-1,2,4-triazol-5(4H)-one and DIPEA in dichloromethane and reaction solution was stirred for 2 h at room temperature. Washed with water and extracted with dichloromethane and solvent was removed. The crude reaction mixture was carried over to the next reaction without further purification. The reaction mixture was diluted by methanol and treated with concentrated HCl and heated it up to 65° C. Column chromatogram produced the desired benzyl 3-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C@@H:9]1[CH2:24][O:25][C:26]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:49]=[N+:50]=[N-:51])[CH2:10][C@@H:9]1[CH2:24][O:25][C:26]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(OC[C@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 92 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl)oxymethyl-4-[(p-toluenesulfonyl)oxy]pyrrolidine 39 (5.1 g, 7.58 mmol) was dissolved in dimethylformamide (50 ml) and diluted with water (5 ml ). To this stirred solution was added sodium azide (0.65 g, 10 mmol) and heated at 80° C. for 8 h. It was cooled and evaporated to dryness. The residue was partitioned between CH2Cl2 (200 ml) and water (100 ml), and extracted in CH2Cl2. The organic extract was washed with brine (50 ml), dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The pure fractions were pooled together and evaporated to give 3.8 g (92%) of a clear oil. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.0CH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-7.80 (m, 9H, Ph).
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[F:25][C:26]([F:31])([F:30])[C:27](O)=[O:28].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[Na+]>C(OCC)(=O)C.O>[F:25][C:26]([F:31])([F:30])[C:27]([NH:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)=[O:28]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 20 g [25.6 millimoles (mmol)] of L-thyroxine (Sigma Chemical Co., St. Louis, Missouri USA) in 240 ml of dry ethyl acetate containing 46 ml of trifluoroacetic acid and 7.6 ml of trifluoroacetic anhydride was stirred at 0° C. for one hour. Upon warming to room temperature and adding 200 ml of H2O, a suspension formed which was then saturated with sodium chloride. The organic phase of the mixture was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give 21.3 g of the N-protected thyroxine derivative (6). A sample was recrystallized from ether-pentane to give fine crystals, m.p. 233°-235° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(Br)cn2)CC1

Procedure:
The product is obtained analogously to Example 3.24a is from 1.5 g (5.28 mmol) 5-bromo-2-iodopyridine and 1.3 mL (11.7 mmol) N-methylpiperazine.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[N+:16]([CH3:27])[C:17]2[C:22]([CH:23]=1)=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][CH:18]=2.[BH4-].[Na+].O>CO>[CH3:12][O:13][C:14]1[CH2:15][N:16]([CH3:27])[C:17]2[C:22]([CH:23]=1)=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][CH:18]=2
Reactant: COc1cc2c([N+](=O)[O-])cccc2[n+](C)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=Cc2c(cccc2[N+](=O)[O-])N(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-1-methyl-5-nitroquinolinium 4-methylbenzenesulfonate in methanol is added sodium borohydride at room temperature. The mixture is stirred at room temperature for 2 h and water is added. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried, filtered and concentrated under reduced pressure to give 3-methoxy-1-methyl-5-nitro-1,2-dihydroquinoline.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[NH:7][C:8](=O)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]=2[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1.P(Br)(Br)([Br:24])=O>>[Br:24][C:8]1[N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]2=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Product: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(Br)nc21
Temperature: 120 °C
Yield: 99.1 %

Procedure:
A mixture of 1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.0 g, 3.4 mmol) and POBr3 (0.962 g, 3.4 mmol) was heated at 120° C. for 3 h. The reaction mixture was cooled to it and poured into rapidly stirred ice cold water to obtain a solid product. The product was collected by filtration and dried under vacuum to yield an off-white solid (1.20 g, 99%). [1H-NMR (CDCl3, 300 MHz) δ 7.58 (s, 1H), 7.54-7.41 (m, 5H), 4.22 (s, 3H); LCMS RtA=1.943 min; [M+H]+=355.9]
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.Cl[CH2:29]I.C([Zn]CC)C>ClCCCl>[C:12]([O:11][C:9](=[O:10])[C:8]1[CH:16]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([O:18][CH2:19][C:20]2([CH3:27])[CH2:25][CH2:24][C:23]3([CH2:29][CH2:26]3)[CH2:22][CH2:21]2)=[CH:6][C:7]=1[F:17])([CH3:14])([CH3:13])[CH3:15]
Reactant: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Reactant: ClCI
Agent: CC[Zn]CC
Solvent: ClCCCl
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate (0.30 g, 0.804 mmol) in 1,2-dichloroethane (2 mL), was added chloroiodomethane (0.21 mL, 2.65 mmol), followed by diethylzinc (1M solution in hexanes, 1.33 mL, 1.33 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then quenched with 1N aqueous hydrochloric acid solution. The aqueous layer was separated and extracted with dichloromethane (3×30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.29 g, 93%) as a colorless oil: MS (ES+) m/z 333.2 (M−55).
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:23])[CH2:4]2)[O:2]1.[Al].CCOCC>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH2:25]1[CH2:1][O:2][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:23])[CH2:4]2)[O:24]1
Reactant: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Agent: [Al]
Solvent: O=C1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[C@H]1CC2(C[C@@H]3CC[C@@H]4[C@H](CC[C@]5(C)C(=O)CC[C@@H]45)[C@]31C)OCCO2
Yield: 93.3 %

Procedure:
55 g of 3,3-ethylenedioxy-17β-hydroxy-1α-methyl-5α-androstane in 550 ml of toluene and 110 ml of cyclohexanone were treated at boiling with a solution of 5.5 g of aluminium isopropylate in 55 ml of toluene and the mixture was heated for 3 hours with slow distillation. The mixture was then treated with ether, washed with ice-cold dilute sulphuric acid and water, evaporated and the residue steam-distilled. After extraction with methylene chloride, the resulting product was recrystallised from diisopropyl ether to give 51 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one of melting point 155.5°-156.6° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=O)C.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[CH:15]1([N:9]2[C:10]([C:11]([F:13])([F:12])[F:14])=[C:6]([CH2:4][OH:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn(C2CC2)c1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1cnn(C2CC2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 96, 1.4 g, 5.64 mmol) in dry toluene (25 mL) was cooled to −78° C. and DIBAL-H (11.8 mL of 1.2 M solution in toluene, 14.1 mmol) was added dropwise to it. The reaction mixture was stirred at −78° C. for 2 hours and poured into 2N HCl (10 mL). This was stirred for a further 4 hours at room temperature followed by extraction with EtOAc (2×25 mL) and the combined organic layers were washed with water (2×10 mL), brine (10 mL) dried (Na2SO4) and evaporated in vacuo to afford the title compound as off white solid (100%, 1.2 g).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])(=[O:7])[CH3:6]
Reactant: N#Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (0.84 mL, 8.87 mmol) was added to a solution of 2-(hydroxymethyl)-6-nitrobenzonitrile (Example 207d) (0.31 g, 1.77 mmol), pyridine (0.86 mL, 10.6 mmol), and DMAP (0.22 g, 1.77 mmol) in CH2Cl2 (10 mL), and stirred for 24 h at rt. The mixture was washed mice with AcOH (1 M, 20 mL), dried with MgSO4, concentrated, and purified by chromatography on silica using CH2Cl2, to give the title compound in amount of 0.36 g (92%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 5.35 (s, 2H), 7.99 (t, J=8.0 Hz, 1H), 8.06 (dd, J=0.8, 8.0 Hz, 1H), 8.37 (dd, J=0.8, 8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[N:3]=1.C(N(CC)CC)C.Cl[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[O:20]([CH2:19][N:3]1[C:2]([CH3:1])=[C:7]([Br:8])[C:6]([CH3:9])=[N:5][C:4]1=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(=O)[nH]c(C)c1Br
Reactant: ClCOc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(=O)n(COc2ccccc2)c(C)c1Br
Temperature: 40 °C

Procedure:
A mixture of 4,6-dimethyl-5-bromopyrimidin-2-one (4.7 mmol) and triethylamine (4.7 mmol) in dichloromethane (60 ml) was heated at 40° C. for dissolution. The solution was then cooled to room temperature and (chloromethoxy)benzene [see Preparation 2] (4.7 mmol) in dichloromethane (15 ml) was added. The resultant mixture was stirred at room temperature for 11/2 h, the solvent distilled off, the mixture triturated with water, the remaining solid extracted with chloroform, the dried (MgSO4) chloroform solution evaporated, the residue triturated with a little ether, the residue redissolved in chloroform and the solution chromatographed on a column of alumina, activity III, using chloroform, Yield 0.35 g (24%), m.p. 120° C. (CCl4). (Found C50.32; H4.15. Calc. for C13H13BrN2O2 : C50.50; H4.25) 1H NMR (CDCl3): δ 2.50 and 2.68 (4-Me and 6-Me), 6.03 (CH2), 6.8- 7.4 (Ph), MS [70 eV, m/z (% rel. int)]. 310/308 (6/7,M), 217(97), 215(100), 174(15), 172(12), 136(20), 135(19), 108(23) 94(19).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26](=[O:33])(=[O:32])[NH:27]C(C)(C)C)[CH:21]=2)[C:8]([O:13]COCCOC)=[C:9]([CH:11]=O)[CH:10]=1)=[O:4].[ClH:34].[NH2:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[NH2:45])[C:39]([NH2:41])=[NH:40]>>[ClH:34].[C:39]([C:38]1[CH:42]=[CH:43][C:44]2[NH:45][C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([S:26](=[O:32])(=[O:33])[NH2:27])[CH:21]=4)[C:8]=3[OH:13])=[N:35][C:36]=2[CH:37]=1)(=[NH:40])[NH2:41]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: COCCOCOc1c(C=O)cc(C(=O)OC)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cccc(S(N)(=O)=O)c4)c3O)nc2c1
Yield: 39 %

Procedure:
Proceeding as in Reference 23, but substituting 3′-tert-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-carboxylic acid methyl ester (1.64 g, 3.42 mmol, 1.0 eq.) and 3,4-diamino-benzamidine hydrochloride (638 mg, 3.42 mmol, 1.0 eq.), gave 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-3′-sulfamoyl-biphenyl-3-carboxylic acid hydrochloride (650 mg) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([O:21]C)=[O:20])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)C12CCCC(NC(=O)c3cncc(C)n3)(CC1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cncc(C(=O)NC23CCCC(C(=O)O)(CC2)C3)n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of methyl 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate (1.28 g, 4.21 mmol) and LiOH (0.15 g, 6.25 mmol) in methanol (30 mL) and H2O (3 mL) was refluxed for two hours. After cooled to room temperature, methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and diethyl ether (50 mL) to remove organic impurities. The aqueous phase was adjusted to pH 1˜2 with 2N aq. HCl and then extracted with dichloromethane (3×50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 1.11 g (91%) of 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid as a white solid. ESI-MS m/z: 290 (M+H)+.
Reaction SMILES: [CH:1]([CH:4](Cl)[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2].[C-:16]#[N:17].[Na+].[OH-].[Na+]>O.C(N(CC)CC)C>[CH:1]([CH:4]([C:16]#[N:17])[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: COc1ccc(C(Cl)C(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(C#N)C(C)C)cc1OC

Procedure:
457.4 g (2 mol) of α-isopropyl-veratryl chloride, 108 g (2.2 mol) of sodium cyanide, 10 mol-% of phase transfer catalyst, 100 ml of water and 800 ml of triethylamine are stirred together for 5 hours at 60° C. After the addition of 60 ml of 30% sodium hydroxide solution and 300 ml of water, the organic phase is separated off. After removal of the triethylamine by distillation, the residue is distilled in a fine vacuum. The distillate obtained is recrystallised from methanol/water.
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5].P(Cl)(Cl)([Cl:25])=O>>[CH3:2][O:3][C:4]([C:6]1[C:7]([Cl:25])=[N:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5]
Reactant: COC(=O)c1c(CCl)c2cc3c(cc2[nH]c1=O)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (360 g, 1.16 mol), prepared as in example 13b, as a suspension in phosphorus oxychloride (1.8 kg). The mixture is heated to reflux generating a black solution. After being heated at reflux for 20 h, the reaction mixture is allowed to cool to ambient temperature and transferred to a 25-L separatory funnel containing 18 L of ice water. After being stirred vigorously for 1.5 h, the precipitate is collected on a Buchner funnel, washed with water (3 L) and dried in vacuo. at 50° C. yielding 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a dark crystalline solid: mp 130°-132° C. 1H NMR (CDCl3, 200 MHz) δ4.05 (s, 3H), 4.42 (s, 4H), 4.81 (s, 2H), 7.50 (s, 2H). Elemental analysis: Calculated for C14H11Cl2NO4 : C 51.24, H 3.38, N 4.27. Found: C 51.10, H 3.34, N 4.33.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:30]([C:31]2[CH:32]=[C:33]([CH2:36][NH2:37])[S:34][CH:35]=2)[N:29]=[C:28]([C:38]([F:41])([F:40])[F:39])[CH:27]=1.CCN(CC)CC.Cl>C(Cl)Cl.CN(C=O)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:30]([C:31]2[CH:32]=[C:33]([CH2:36][NH:37][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[S:34][CH:35]=2)[N:29]=[C:28]([C:38]([F:40])([F:41])[F:39])[CH:27]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 36 h
Yield: 49 %

Procedure:
(S)-2,5-Dioxopyrrolidin-1-yl 2-(tert-butoxycarbonylamino)propanoate (130 mg, 0.45 mmol) was added to amine 5 (110 mg, 0.35 mmol) and Et3N (94.4 mg, 130 μL, 0.93 mmol) in DCM (2 mL) and DMF (0.2 mL) and the mixture was stirred at room temperature for 36 h. DCM was added followed by 1N HCl and the organic layer was separated and washed with H2O, then with saturated NaHCO3, dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography (Biotage, 25+S column) eluting with 0-50% EtOAc/hexanes. Compound 6 was obtained in 49% yield as a white solid. LRMS (ESI): calc. 484.5; found 507.1 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCO
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: Cc1cc(F)ccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 16 to obtain 485 mg of desired compound as solid in 95% of yield.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.O1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:12]1([N:8]=[C:1]=[N:3][CH:7]2[CH2:6][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The compounds of Formula I wherein n is two, R2 is hydrogen, R3 is phenyl or substituted phenyl, and X is a tetrazole are prepared as set forth in Chart V. Compound (32) is prepared according to the method of Paganelli (Tett. Lett. 1991; 32: 2807-2810) by a transition metal catalyzed Michael addition of benzyl cyanide to methyl acrylate. Compound (32) is then treated with (n-Bu)3SnN3 in refluxing dioxane to give the tetrazole (33), which is then alkylated with an alkyl halide, R4 halo, e.g., R4Br, wherein R4 is as defined in Formula I, in acetonitrile employing Et3N as base, giving a mixture of regioisomers (34) and (35) which are separated by flash chromatography. Hydrolysis of each ester with ethanolic NaOH at room temperature gives the respective acids (36) and (38). The acids are then coupled with an appropriate amine of the formula R1NH2 wherein R1 is as defined in Formula I employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl at 0° C. as coupling agent to give the amides (37) and (39).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])#[N:2].[OH2:11]>>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([OH:11])=[O:6])#[N:2]
Reactant: O
Reactant: N#Cc1ccccc1C=O
Product: N#Cc1ccccc1C(=O)O

Procedure:
Moreover, the present inventors have found that reaction of the cyanobenzaldehyde compounds as starting materials and a hypohalogenous compound in water or a mixed solvent of water and an aprotic polar solvent affords cyanobenzoic acid compounds in a high purity and in a high yield.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:8]([CH3:21])[C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](C2N=C(N3CCOCC3)C3SC(CN4CCC(C(NC)=O)CC4)=CC=3N=2)=[CH:31][N:30]=1>>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)=[N:7][C:6]=3[C:8]=2[CH3:21])[CH3:20])[CH2:14][CH2:15]1
Reactant: CNC(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 5 %

Procedure:
N-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine following Example 115 (0.23 mmol) was reacted using General Procedure A: Suzuki Coupling to give 190 (TFA salt) in a 5% yield after reverse-phase HPLC purification. MS (Q1) 469 (M)+.