Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][C:12]2[C@@H:11]3[CH2:14][C@@H:10]3[CH2:9][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Li+].CO>C1COCC1>[CH2:14]1[C@@H:10]2[CH2:9][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:13][C:12]=3[C@H:11]12
Reactant: CCOC(=O)c1cc2c([nH]1)[C@@H]1C[C@@H]1C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)[C@@H]1C[C@@H]1C2

Procedure:
The title compound was synthesized from (1aR,5aR)-1a,2,5,5a-tetrahydro-1H-2-aza-cyclopropa[α]pentalene-3-carboxylic acid ethyl ester (115 mg, 0.6 mmol) and lithium hydroxide (252 mg, 6.0 mmol in 5 mL water) according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The resulting product was purified by chromatography eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 27 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.31-0.39 (m, 1H), 1.06-1.16 (m, 1H), 2.04-2.19 (m, 2H), 2.63 (d, J=15.67 Hz, 1H), 2.84 (dd, J=15.62, 6.35 Hz, 1H), 6.73 (s, 1H), 8.97 (br. s, 1H). LCMS m/e 164 (M+H). Purity>85% (HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:27][O:19][C:18](=[O:20])[CH:17]([C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (250 mg, 0.67 mmol; example 5.1) in dry DCM (7 mL) was added oxalyl chloride (0.14 ml, 1.67 mmol) drop wise at 0° C. followed by 1 drop DMF and the reaction mixture was stirred at that temperature for 30 min. Ice-bath was removed and stirring was continued for 3.5 h at room temperature. DCM and excess oxalyl chloride was then removed under reduced pressure and MeOH (2 ml) was then added to it at 0° C. After being stirring the reaction mixture at rt for 1 h, TLC shows formation of a new spot. MeOH was removed under vacuo and crude material was passed through a bed of silica gel (SiO2, 100-200 mesh, EtOAc:hexane 30:70) to give the title compound as colorless liquid (250 mg, 95.5%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]1[NH:10][NH2:11].CCO[C:15](OCC)(OCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[NH2:11][N:10]1[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[N:2]2[N:1]=[C:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(=O)n(N)c(NN)n1
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CCCCO
Product: Cc1cc(=O)n2nc(-c3ccccc3)n(N)c2n1

Procedure:
A mixture of 2.0 g of 3-amino-2-hydrazino-6-methyl-4(3H)-pyrimidinone, 10 ml of triethyl orthobenzoate and 20 ml of n-butanol was reacted as described in Example 1, giving 1.27 g of the desired intermediate, mp 195° C. (dec.).
Reaction SMILES: OC1C=C(O)C=C[C:3]=1[CH:9]([C:20]([CH:22]([C:33]1[CH:38]=CC(O)=CC=1O)[C:23]1C=CC(OC)=[C:25]([O:31]C)[CH:24]=1)=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([O:43]C([O-])[O-])C.N1CCOCC1>CN(C)C=O>[OH:31][C:25]1[CH:24]=[C:23]2[C:22]([C:20](=[O:21])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:3][O:43]2)=[CH:33][CH:38]=1
Reactant: CCOC([O-])[O-]
Reactant: COc1ccc(C(C(=O)C(c2ccc(OC)c(OC)c2)c2ccc(O)cc2O)c2ccc(O)cc2O)cc1OC
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
14.4 g (0.05 mole) of 2,4-dihydroxy-phenyl-(3',4'-dimethoxy-benzyl)-ketone are reacted with 10.5 g (0.07 mole) ethyl-orthoformate in 10 ml of dimethyl-formamide in the presence of 1 ml morpholine. The reaction mixture is maintained at 80°-85° C., and in the second hour a solid precipitates. After 6 hours 1OO ml of chloroform are added to the mixture, the precipitated substance is filtered and dried. 7-hydroxy-3',4'-dimethoxy-isoflavone is obtained.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)CC(O)=CC(=O)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran. After addition of the phenone, the reaction was stirred 15 minutes at -78° C. and 2 hours at room temperature. The crude reaction was flash chromatographed using hexane/ethyl acetate 6/40-40/60 as eluent. The solid was triturated from diethyl ether (m.p. 123.5°-125° C.). 1H NMR (CDCl3) δ 0.81 (d, 3 H), 0.89 (d, 3 H), 1.6-1.7 (M, 1 H), 1.91 (m, 2 H), 2.90 (d, 1 H), 2.95 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.25-7.45 (m, 5 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]([CH3:46])[C:42]([SH:45])=[N:43][N:44]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].[BH4-]>O1CCCC1.C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]2[CH:25]=[CH:26][C:27]([S:45][C:42]3[N:41]([CH3:46])[C:40]([C:37]4[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=4)=[N:44][N:43]=3)=[CH:28][C:9]=2[O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:14][CH:15]=1)[CH3:24]
Reactant: CCCCCCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Reactant: Cn1c(S)nnc1-c1ccc(C(C)(C)C)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)OCC)cc1

Procedure:
A solution of ethyl [4-(2-heptyloxy-4-iodo benzylamino)phenyl]acetate obtained in Step d (4.11 g, 8.07 mmol) in a mixture of tetrahydrofuran (THF) (18 ml) and ethanol (18 ml) is added dropwise to a mixture of 5-(4-tert-butylphenyl)-4-methyl-4H-[1,2,4]-triazole-3-thiol (2.99 g, 12.1 mmol), bis(bipyridine)nickel (II) bromide (106 mg, 0.2 mmol) (Organometallics, 4, (1985), 657-661) and 9.68 g of borohydride polymer supported on Amberlite® IRA400 resin at 2.5 mmol/g (Aldrich) in 18 ml of a mixture of THF and ethanol 50:50. The mixture is heated for 20 hours under reflux, and then filtered at room temperature. The filtrate is concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 7:3 mixture. After evaporation of the solvents, 4.58 g (90%) of the expected compound are recovered in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[CH2:6][O:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[CH2:6][O:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCc1nccn1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1nccn1-2
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
A mixture of methyl 7-amino-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (Intermediate 26, 0.379 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.466 g) in pyridine (10 mL) and DCM (10 mL) was stirred at room temperature for 17 hours. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) was added and the mixture was stirred at room temperature for 5 hours. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM and water and passed through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with ethyl acetate to give a white solid which was triturated with ether to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (0.603 g) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 55 (80 mg, 0.17 mmol) is treated with acid chloride 8 (55 mg, 0.21 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:32]#[N:33])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.C(N(CC)CC)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl>[C:26]([O:25][C:24]([N:23]([CH3:31])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH:2]([NH:1][C:42](=[O:43])[O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:32]#[N:33])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)C#N)CC4)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)NC(=O)OCc2ccccc2)CC4)CC1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(2-amino-2-cyanoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (800 mg, 1.70 mmol, 1.00 equiv) and triethylamine (340 mg, 3.36 mmol, 2.00 equiv) in dichloromethane (50 mL) was added dropwise a solution of benzyl chloroformate (320 mg, 1.88 mmol, 1.10 equiv) in 10 mL of DCM at 0° C. The resulting solution was stirred for 30 min at this temperature and then quenched with water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to give benzyl N-[2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-cyano ethyl]carbamate (0.5 g, 49%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](I)[CH:26]([CH3:28])[CH3:27]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]2[CH2:25][CH:26]([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CI
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1CC(C)C

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 9 using ethyl 4-benzyloxy-1H-indole-2-carboxylate (10.0 g), sodium hydride (1.6 g) and isobutyl iodide (3.3 ml), the title compound (6.0 g) was obtained as a brown oil.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.CN(C=O)C.[H-].[Na+]>CO>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
To a mixture of Solketal (66.1 g, 0.5 mol), 1-bromotetradecane (159.4 g, 0.575 mol), and DMF (800 ml) was added 60% NaH (26.0 g, 0.65 mol) in oil dispersion in 3 portions for 1 hr. The mixture was stirred at room temperature for 1 day and methanol (20 ml) was added to destroy the excess NaH. This was then poured into 1500 ml of ice-water and the aqueous layer was extracted with hexanes (2000 ml). The combined organic layers were evaporated to dryness and the oily residue was refluxed in 10% HCl/methanol (conc. HCl, 250 ml and methanol, 675 ml) for 30 min followed by stirring at room temperature overnight. The white flaky solid was filtered and washed with methanol (122 g). The additional product was obtained from the filtrate (5.7 g); Total 127.7 g (88.5%). The crude product was recrystallized from diethyl ether; Yield 99.7 g (69.1%), mp 57°-58° C.
Reaction SMILES: C=O.N.[N:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[CH3:12].N1C(C)=CC=C(C)[C:14]=1C>C(C(C)=O)C>[CH3:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[C:9]([CH3:14])[N:4]=1
Reactant: Cc1cnc(C)c(C)c1
Reactant: Cc1ccc(C)c(C)n1
Agent: C=O
Agent: N
Solvent: CCC(C)=O
Product: Cc1cc(C)c(C)nc1C

Procedure:
When the process of the present invention is performed in the form of a fixed bed, the catalyst of the present invention is packed in a reactor and heated to a reaction temperature. Then, the mixture of methyl ethyl ketone, formaldehyde and ammonia was allowed to proceed through the gas phase catalytic reaction while maintaining the suitable reaction temperature. Thus, a reaction product containing 2,3,5-collidine, 2,3,6-collidine and 2,3,5,6-tetramethylpyridine is obtained.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1.O1CCOCC1.Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CN(C)C=O>[F:26][C:22](=[C:23]([F:25])[F:24])[CH2:21][CH2:20][S:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2nnc(S)o2)o1
Reactant: FC(F)=C(F)CCBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2nnc(SCCC(F)=C(F)F)o2)o1
Yield: 54.5 %

Procedure:
3.7 g of 2-mercapto-5-(2-methyl-1,3,4-oxadiazol-5-yl)-1,3,4-oxadiazole according to Example H1 are initially introduced into a mixture of 36 ml of dioxane and 4 ml of dimethylformamide, and 2.24 g of potassium t-butylate are added, while stirring. 4.2 g of 4-bromo-1,1,2-trifluorobut-1-ene are added dropwise and the mixture is stirred overnight at room temperature. After the salts have been filtered off, the solvents are distilled off in vacuo, the residue is taken up in methylene chloride, the solution is washed with water and 1-normal sodium hydroxide solution in succession and the solvent is evaporated off in vacuo. 3.2 g of the desired compound of melting point 77°-79° C. are obtained as the residue.
Reaction SMILES: [N:1]1([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[N:1]1([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)N2CCOCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexane-carboxylate (860 mg) obtained in Reference Example 82(1) is dissolved in methanol (40 ml), and thereto is added 4 N aqueous sodium hydroxide solution (1.68 ml). The mixture is then stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure. The residue is diluted with ice-water, neutralized with 10% hydrochloric acid and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is concentrated under reduced pressure to give title compound (638 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(C([O-])=O)[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1.[Na+].Cl>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=C(O)C1=CC(C(=O)[O-])(c2ccccn2)Nc2ccccc21
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(-c2ccccn2)nc2ccccc12

Procedure:
The free acid is prepared by neutralizing an aqueous solution of the sodium 2-(2-pyridyl)-4-carboxyquinoline carboxylate 3 with 10% HCl. The acid is somewhat soluble in acidic solution, and care should be taken not to overacidify; a pH of 7 is optimum. The solid is filtered, washed with 40 mL of acetone and allowed to air dry.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.Cl.C([O-])(=O)C.[NH4+].C(N(CC)C(C)C)(C)C>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN1CCC(C=O)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)CC1
Yield: 21 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 1-Methyl-piperidine-4-carbaldehyde; hydrochloride (46.0 mg, 0.281 mmol), Ammonium acetate (39.4 mg, 0.511 mmol), and N,N-Diisopropylethylamine (53.37 uL, 0.3064 mmol) were reacted to produce 21.99 mg (21%) of the title compound. (300 MHz, DMSO-d6) 12.52 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.18 (s, 1H), 6.95 (d, J=9 Hz, 1H), 6.29 (m, 2H), 5.09 (t, J=17 Hz, 8.5 Hz, 1H), 2.87-2.54 (m, 7H), 2.18 (s, 3H), 1.98 (m, 4H), 1.81 (m, 2H), 1.38 (d, J=8 Hz, 1H). MS=499 (M+H), HPLC: 2.47 min. (G Method)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH:35]=[O:36])[N:7]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C=O)n3)c2)cc1

Procedure:
A solution of 6-bromo-4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (15.1 mmol) in 100 mL of dry THF is added dropwise to a solution of n-butyl lithium (15.5 mmol) in 20 mL of tetrahydrofuran (THF) at −78° C. under N2 over 12 minutes. After 10 minutes the reaction mixture is treated with dimethylformamide (7.5 mL) in THF (15 mL), and quenched after 15 minutes with aqueous 10% HCl. The product is extracted into cold chloroform which is washed with saturated sodium chloride solution, filtered, and the solvent is evaporated. The residue is triturated with CH3CN, filtered, and recrystallized from ethyl acetate to provide the desired compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:26]=[CH:25][C:6](/[CH:7]=[C:8]2/[C:9]([CH3:24])=[C:10]([CH2:20][C:21](O)=[O:22])[C:11]3[C:16]/2=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=3)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:30])=O>C1COCC1>[CH3:1][S:2][C:3]1[CH:26]=[CH:25][C:6](/[CH:7]=[C:8]2/[C:9]([CH3:24])=[C:10]([CH2:20][C:21]([Cl:30])=[O:22])[C:11]3[C:16]/2=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=3)=[CH:5][CH:4]=1
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(N(C)C)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(N(C)C)ccc32)cc1

Procedure:
(Z)-1-(p-methylthiobenzylidene)-5-dimethylamino-2-methyl-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH3:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:13])(=[O:11])=[O:10]
Reactant: N
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1c(Cl)cccc1Cl
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2,6-dichlorobenzenesulfonyl chloride (10.50 g, 42.77 mmol) in 100 mL of pyridine was added dropwise to 100 mL of pyridine while anhydrous ammonia gas was bubbled through the solution. After 4 hours at 0° C., the mixture was acidified to pH>1 with 6N aq. HCl, then extracted with ethyl acetate. The combined organic layer was then dried (Na2SO4) and concentrated to give the desired product (8.69 g, 90%). EI-MS (m/z) 225.0, 227.1 (M−).
Reaction SMILES: [Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[OH:12])[CH2:3]1)[CH2:9]2.CC(C)([O-])C.[K+].[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>CS(C)=O.O>[Cl:19][C:20]1[C:21]([O:12][CH:5]2[CH:4]3[CH2:10][CH:8]4[CH2:9][C:2]([Cl:1])([CH2:11][CH:6]2[CH2:7]4)[CH2:3]3)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: OC1C2CC3CC1CC(Cl)(C3)C2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OC2C3CC4CC2CC(Cl)(C4)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 5-chloroadamantan-2-ol (2.00 g, 10.70 mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassium tert-butoxide (3.01 g, 26.80 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (2.06 g, 10.70 mmol) was added to the reaction mixture, stirring was continued for 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueous hydrochloric acid solution and diluted with water (100 mL), the white precipitate was filtered, washed with water and dried to afforded the title compound as colorless solid (3.30 g, 86%), containing o-substituted regioisomer, which was used for next step without further purification: MS (ES+) m/z 359.2, 361.2 (M+1), MS (ES−) m/z 357.1, 359.1 (M−1).