Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[NH2:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O.C1N=CN(C(N2C=NC=C2)=O)C=1>O>[Cl:29][C:27]1[CH:28]=[C:20]2[C:21]([C:22](=[O:24])[N:16]([S:13]([C:10]3[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=3)(=[O:14])=[O:15])[C:17](=[O:18])[NH:19]2)=[CH:25][CH:26]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Following Synthesis Method (A), into 200 ml of anhydrous tetrahydrofuran (hereinafter referred to as THF) was dissolved 4.90 g (22.5 mmol) of 4-chlorobenzenesulfonylisocyanate, then 3.51 g (20.5 mmol) of 2-amino-4-chlorobenzoic acid was added and the mixture was stirred at room temperature for two hours. The reaction solution was cooled by ice water, then 3.98 g (24.55 mmol) of CDI was added and the mixture was stirred under ice cooling for 30 minutes. An excess amount of water was poured into the reaction solution, then the precipitated crystal was obtained by filtration and the obtained crystal was washed by water, then was washed by ethyl acetate to obtain 5.03 g of the above-identified compound (yield 66.5%). Properties: colorless crystal, Melting point: 286°-287° C., PMR (δppm, DMSO-d6): 7.12 (1H,s), 7.23 (1H,d), 7.26 (2H,d), 7.86 (1H,d), 8.17 (2H,d), 11.71 (1H,br).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([O:10]COC)=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1>C(O)(=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCc1cc(C2CC2)ccc1OCOC
Solvent: CC(=O)O
Product: CCc1cc(C2CC2)ccc1O
Temperature: 0 °C
Yield: 92.2 %

Procedure:
A solution of 12.0 g of 4-cyclopropyl-2-ethyl-1-methoxymethoxy-benzene in 240 ml of 2N acetic acid was stirred for 24 hours at 90° C. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phases were washed with water, saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed over silica gel and gave 8.7 g of 4-cyclopropyl-2-ethyl-phenol; MS (EI) m/z 162 (M), 147 (M−CH3).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:33][C:34]1[NH:35][C:36]2[NH:37][CH2:38][CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[NH:40][C:41]=2[C:42](=[O:44])[N:43]=1>C(Cl)Cl.N1C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:13]([N:40]1[CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[CH2:38][NH:37][C:36]2[NH:35][C:34]([NH2:33])=[N:43][C:42](=[O:44])[C:41]1=2)=[O:15])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1c2c([nH]c(N)nc2=O)NCC1C(O)C(C)O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of N-Boc-L-Valine (4.56 g, 21 mmol) in DCM (15 ml) at 0° C. was added a solution of DCC (2.17 g, 10.5 mmol) in DCM (10 ml). The resulting solution was stirred for 1 h after which a white precipitate formed. The white solid was filtered and filtrate added to a stirred solution of 2-amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (3.0 g, 9.55 mmol) dissolved in pyridine (80 mL). The mixture was stirred at room temperature under an atmosphere of nitrogen for 1.5 h. The reaction mixture was quenched by addition of methanol (20 ml). The solvent was evaporated in vacuo and the residue purified by preparative RP-HPLC to give the sub-title product as a tan solid (3.2 g, 76%). MS: ESI (positive): 441 (M+H).
Reaction SMILES: [BrH:1].[OH-].[Na+].[OH:4][CH2:5][C@@H:6]1[CH:21]=[C:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:8]([CH3:9])[CH2:7]1.N>Br.CS(C)=O.CS(C)=O>[Br:1][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C:20]([C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:21][C@@H:6]([CH2:5][OH:4])[CH2:7][N:8]1[CH3:9]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: Br
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Dry gaseous hydrogen bromide is introduced into 100 ml of anhydrous dimethylsulfoxide at room temperature. The quantity of the introduced hydrogen bromide gas is measured by titrating with 0.1N sodium hydroxide solution. The hydrogen bromide is introduced until the concentration of the gas reaches 0.0003-0.0005 mole/ml. One g (0.003937 mole) of lysergol is dissolved in an aliquot amount of this hydrogen bromide-dimethylsulfoxide mixture which contains 12 equivalents of hydrogen bromide. After complete dissolution, this mixture is stirred at room temperature for 20 minutes, then poured into a 5-fold volume of ice-water. Thereafter, the solution is made alkaline by adding aqueous ammonia up to a pH value of 8.9, the precipitate is filtered off, washed with water, dried and purified on a Kieselgel column by using an 8:2 mixture of chloroform and methanol to give the named compound in a yield of 0.76 g (0.00228 mole, 58%), m.p.: 193° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([OH:60])=[O:59])[CH:53]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[CH2:67](Cl)Cl.C[Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([O:60][CH3:67])=[O:59])[CH:53]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(C(=O)O)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(C(=O)OC)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (7 mg) in methylene chloride: methanol (2:1, 0.75 mL) at 0° C. was added a methylene chloride solution of trimethylsilyldiazomethane (10% by weight) until a yellow colored persisted. The mixture was then warmed to room temperature, concentrated in vacuo, and purified by flash chromatography on silica gel (acetone:hexane (1:2)) to give the title compound (5.5 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[C:5]([CH3:10])=[N:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccnc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOc1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C

Procedure:
3-Ethoxy-2-methylpyridine (132.5 g) was added dropwise to concentrated sulphuric acid (530 ml) with stirring and cooling to keep the mixture below 10° C. A mixture of concentrated nitric acid (81 ml) and concentrated sulphuric acid (97 ml) was added dropwise over 4 hours, keeping the temperature below 5° C. The reaction mixture was allowed to warm up slowly to ambient temperature and then added in portions to ice/water (2.5 l). The solid was collected by filtration, washed with water and dried under vacuum at 50° C. to give 3-ethoxy-2-methyl-6-nitropyridine, m.p. 82°-84° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:31])=[O:32])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[C:15]([NH2:49])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 1 h

Procedure:
7-Benzyloxy-1-[4-(1,1-dioxoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (2.83 g) was dissolved in chloroform (30 mL). 3-Chloroperoxybenzoic acid (60% pure, 2.21 g, 7.7 mmol) was added in one portion and the mixture was stirred for 1 hour. Ammonium hydroxide (30 mL) was added and the biphasic mixture was stirred for 20 minutes. p-Toluenesulfonyl chloride (1.07 g, 5.6 mmol) was added in one portion and the reaction was stirred for 16 hours. A white precipitate formed. The mixture was diluted with dichloromethane (solid remains in the organic fraction) and the layers were separated. The organic fraction was washed with 5% aqueous sodium bicarbonate (solid moves to the aqueous fraction). The layers were separated, followed by filtration of the solid from the aqueous fraction. The solid was sequentially washed with water and diethyl ether; slurried in acetonitrile; filtered; and dried to yield 1.5 g of 7-benzyloxy-1-[4-(1,1-dioxoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 225-227° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.00 g (17.7 mmol/1 eq) of L-threonine methyl ester hydrochloride are suspended in 50 ml of methanol, and 7.4 ml (53 mmol/3 eq) of triethylamine are added thereto. After 10 minutes, the mixture is cooled to 0° C. and the benzoyl chloride (2.74 g/190.5 mmol/1.1 eq) is added. Stirring is carried out at 0° C. for a further two hours. The solvent is then removed using a rotary evaporator. The solid that remains behind is taken up with ethyl acetate/H2O (50/20 ml). The aqueous phase is separated off and extracted by shaking twice more with ethyl acetate (30 ml each time). The combined organic phases are washed with 15 ml each of H2O and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.07 g (97% of theory) of a white solid are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: Cc1nc(C(=O)N2CCCC(C)C2CN)c(-c2ccc(F)cc2)s1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chloro-5-(trifluoromethyl)pyridine, and K2CO3 in DMAC was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a pale yellow oil which solidified. MS (ESI) 493.01 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH2:14][CH2:15][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:17][NH2:18]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH2:14][O:13][CH3:12])=[O:6]
Reactant: COCCC(CN)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: COCCC(CNC(=O)c1cccc(Cl)c1Cl)c1cnc(C(F)(F)F)nc1

Procedure:
From 2,3-dichlorobenzoic acid and 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butan-1-amine. LCMS (MH+): m/z=422.0, tR (minutes, Method F)=2.73
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CS[C:17](=[N:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[NH:18][C:19]#[N:20].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:17]([NH:18][C:19]#[N:20])=[N:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:10]=1
Reactant: NCCCCCCOc1cccnc1
Reactant: CSC(=Nc1ccncc1)NC#N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1ccncc1)NCCCCCCOc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[6-amino-1-hexyl-oxy]-pyridine (150 mg), S-methyl-N-cyano-N′-4-pyridyl-isothiourea (123 mg), triethylamine (0.18 ml), 4-(N,N-dimethylamino)-pyridine (3.5 mg) and pyridine (5 ml) was stirred overnight at 60° C. After cooling to room temperature the pyridine was removed by evaporation twice with toluene in vacuo and the residue was distributed between water and ethyl acetate. The organic phase was dried and evaporated to yield a crude product which was purified by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (40:10:2.5) as eluent. The pure fractions were pooled and evaporated to give the title compound which crystallised from ethyl acetate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14]3=[O:29])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH:21]1([C:17]2[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14](=[O:29])[N:13]3[C:18]=2[C:19]([CH3:20])=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=2)[CH:11]=[CH:12]3)[CH2:22][CH2:23]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(C)=O)cc3)ccn2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(C)O)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
50 mg of ethyl 8-(4-acetylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 3) was dissolved in 1 ml of ethanol. 9 mg of sodium borohydride was added to the obtained solution, and they were stirred at room temperature for 14 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=100/3) to obtain 35 mg of ethyl 1-cyclopropyl-8-[4-(1-hydroxyethyl)phenyl]-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:40])([CH3:39])[CH2:31][O:32]C1CCCCO1)([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([CH3:24])[CH2:16][O:17]C1CCCCO1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C>Cl.O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:39])([CH3:40])[CH2:31][OH:32])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:25])[CH2:16][OH:17])[C:4]([O:3][CH2:1][CH3:2])=[O:41])[CH3:10]
Reactant: CCOC(=O)C(CCCCC(C)(C)COC1CCCCO1)(CCCCC(C)(C)COC1CCCCO1)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Yield: 83.5 %

Procedure:
A solution of 2,2-bis[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]malonic acid diethyl ester (2.92 g, 5.0 mmol) in concentrated hydrochloric acid (2.4 mL) and water (1.6 mL) was heated at reflux for 1 h. Ethanol (8.2 mL) was added and the reaction mixture was heated at reflux for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to afford 2,2-bis(6-hydroxy-5,5-dimethylhexyl)malonic acid diethyl ester (1.74 g, 84%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.13 (q, 4 H, J=7.2 Hz), 3.25 (s, 4 H), 2.42 (s, 2 H), 1.90-1.75 (m, 4 H), 1.30-1.12 (m, 18 H), 0.84 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 172.0, 71.7, 60.9, 57.4, 38.2, 34.9, 32.1, 24.8, 24.0, 23.7, 14.0. HRMS (LSIMS, gly): Calcd. for C23H45O6 (MH+): 417.3216, found: 417.3210.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@@H:5]([O:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:32][CH3:33])[C:4]([OH:34])=[O:3])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccc(C#N)cc3)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(C#N)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4′-cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Step A) via the standard hydrolysis procedure C (NaOH). 1H-NMR (MeOD, 300.15 MHz): δ 7.77 (s, 4H), 7.64 (d, 2H, J=8.7), 7.18 (d, 2H, J=8.5), 7.07 (d, 2H, J=8.7), 6.86 (d, 2H, J=8.3), 4.24 (t, 2H, J=6.3), 4.17 (t, 2H, J=6.3), 3.84–3.74 (m, 1H), 3.03–2.81 (m, 2H), 2.26 (qn, 2H, J=6.0).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][C@H:30]1[CH3:43]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:13])[F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][C@@H:30]4[CH3:43])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1N
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1R*,3R*,4R*)-4-amino-3-methylcyclohexyl]carbamate (example C11) the title compound is obtained as pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13]O.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in MeOH (10 mL, 247 mmol) was added sulfurous dichloride (0.232 mL, 3.22 mmol). The resulting mixture was stirred at 60° C. After 3 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow oil of methyl 2-(4-bromo-3-fluorophenyl)acetate (500 mg, 1.774 mmol, 83.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.53 (t, J=8.0 Hz, 1H), 7.15 (dd, J=9.8, 1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 3.75-3.61 (m, 5H); ES-LCMS m/z 248.9 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH:8]=1.[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:1][CH2:2][C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH:4]=1
Reactant: CN1CC=C(CO)CC1
Reactant: Oc1ccccc1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC=C(COc2ccccc2I)CC1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
4-(Hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1, 5.63 g, 0.044 mol), 2-iodophenol (7.80 g, 0.035 mol) and triphenylphosphine (11.61 g, 0.044 mol) were stirred in dry THF (200 ml) under Ar as diethyl azodicarboxylate (7.0 ml, 0.044 mol) was added portionwise. The solution was stirred for 1 h, concentrated, diluted with ethyl acetate, and extracted with dil. HCl. The extract was basified (sat. K2CO3 solution) and extracted with ethyl acetate. This organic extract was dried (Na2SO4) and evaporated to give a brown oil. Purification by chromatography on silica gel, eluting with 0-10% methanol/chloroform (gradient) gave the title compound (7.65 g, 65%) as an amber oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccncc1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and isonicotinoyl chloride hydrochloride (89 mg; 0.50 mmol; 2.0 eq.) as a white powder (39.4 mg, 51%). HPLC, Rt: 1.90 min. (purity 97.2%). LC/MS, M+(ESI): 306.4, M−(ESI): 304.4.