Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[CH2:19]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH2:28]O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:28][CH2:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(O)cc21
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(OCCN(Cc3ccccc3)Cc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
Tert-butyl 3-chloro-6-hydroxyindazole-1-carboxylate (4.3611 g) which can be prepared according to the method described in Reference example 39, etc. and 2-(dibenzylamino)ethanol (4.1529 g; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated THF (100 mL), added with triphenylphosphine (7.9370 g; manufactured by Kanto Chemical Co., Inc.) and TMAD (5.2270 g; manufactured by Masuda Chemical Industries Co., Ltd.), and then stirred overnight at room temperature. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-D”; n-hexane:ethyl acetate=90:10→75:25) to obtain the title compound (7.1028 g).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[N:6]1([C:11]2([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18](=[O:25])[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[CH:9][N:8]=[CH:7]1>C(Cl)Cl>[OH:5][P:1]([O:4][P:1]([OH:4])([OH:3])=[O:2])(=[O:3])[OH:2].[N:6]1([C:11]2([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:25])[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=P(O)(O)O
Agent: Cc1ccc(C2(n3ccnc3)c3ccccc3C(=O)c3ccccc32)cc1
Solvent: ClCCl
Product: O=P(O)(O)OP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.54 g of 85% strength phosphoric acid are added dropwise to 6 g (0.0172 mol) of 9,10-dihydro-9-imidazol-1-yl-9-(4-methylphenyl)-10-oxo-anthracene (compare Example 1) in 200 ml of methylene chloride and the mixture is subsequently stirred for 2 hours at room temperature. The solid which separates out is filtered off, washed with 150 ml of ether and 150 ml of acetone and dried over phosphorus pentoxide at 70° C. 7.8 g (83% of theory) of 9,10-dihydro-9-imidazol-1-yl-9-(4-methylphenyl)-10-oxo-anthracene diphosphate of melting point 171°-173° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)c1

Procedure:
N-tert-Butyl-3-{4-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.10) (0.43 g, 1.11 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.21 mmol) according to the general procedure VI. Obtained as a light brown solid (0.37 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:18](=O)[CH3:19])[C:11]([O:13][CH:14]1[CH2:17][O:16][CH2:15]1)=[O:12].[NH2:21][C:22]([CH2:28][F:29])=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH:14]2[CH2:17][O:16][CH2:15]2)=[O:12])=[C:18]([CH3:19])[NH:21][C:22]([CH2:28][F:29])=[C:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1COC1
Reactant: COC(=O)C=C(N)CF
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC2COC2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of the product of step (a) (2.9 g, 7.6 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (1 g, 7.6 mmoles) in dry tert-butanol (20 ml) was heated to 60° (oil bath temperature) for 16 hours. The solution was allowed to cool to room temperature and the solvent removed in vacuo. Chromatography on silica, eluting with dichloromethane/ethyl acetate mixtures afforded the title compound as an oil which crystallised on addition of petroleum ether (60°-80° ). The solid was recrystallised from petroleum ether (60°-80° )/acetone to afford the title compound 1.03 g, mp 155°-6°.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>O1CCCC1>[NH:10]1[C:9]2[CH:13]=[CH:14][C:6]([CH:5]=[CH:4][CH2:3][OH:2])=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: COC(=O)C=Cc1ccc2[nH]cnc2c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC=Cc1ccc2[nH]cnc2c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 102.1 %

Procedure:
To a solution of 3-(1H-benzoimidazol-5-yl)-acrylic acid methyl ester (50 mg in 1 mL dry tetrahydrofuran) at -78° C. was added 1.24 nL of a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran and the mixture stirred at -78° C. for 4 hours followed by warming to -40° C. for an additional 4 hours. The reaction was quenched by addition of aqueous methanol, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 87:13) to give the title compound (44 mg).
Reaction SMILES: O[C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2c[nH]c(Cl)n2)cc1
Reaction time: 24 h

Procedure:
A mixture to 2-hydroxy-4-(4-nitro-phenyl)-1H-imidazole (15 g) and phosphorous oxychloride (750 ml) was refluxed, while stirring, for 24 hours. The solution was then evaporated to dryness, the residue was adjusted to pH 6.5 with a H2PO4- /HPO4-- buffer, and extracted with methylene chloride. After drying, the organic solution was evaporated, and the crude product was chromatographed on silica gel to give 6.7 g of the title compound. M.p. 136°-138° C.
Reaction SMILES: [CH3:1][C:2]([CH3:51])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:50])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:49])=[CH:11]\[CH2:12][CH2:13]/[C:14](/[CH3:48])=[CH:15]\[CH2:16][CH2:17]/[C:18](/[CH3:47])=[CH:19]\[CH2:20][CH2:21]/[C:22](/[CH3:46])=[CH:23]\[CH2:24][CH2:25]/[C:26](/[CH3:45])=[CH:27]\[CH2:28][CH2:29]/[C:30](/[CH3:44])=[CH:31]\[CH2:32][CH2:33]/[C:34](/[CH3:43])=[CH:35]\[CH2:36][CH2:37]/[C:38](/[CH3:42])=[CH:39]\[CH2:40][OH:41].[C:52](Cl)(=[O:55])[CH:53]=[CH2:54]>N1C=CC=CC=1.CCCCCC>[C:52]([O:41][CH2:40][CH:39]=[C:38]([CH3:42])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:43])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:44])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:45])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:46])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:47])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:48])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:49])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:50])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:51])[CH3:1])(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)Cl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CO
Solvent: c1ccncc1
Solvent: CCCCCC
Product: C=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.0 Grams of decaprenol were dissolved in 50 ml of pyridine. The solution was added with 15% solution of 2.1 g of acrylic acid chloride in pyridine at room temperature over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the rection. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentate was purified by chromatography with 80 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain a white solid (m.p. 32.0°-32.8° C.). Yield 5.8 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([CH3:13])[CH2:10]2)=[CH:4][N:3]=1.[NH2:14][C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Br:21][C:19]1[CH:20]=[C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:12][N:11]([CH3:13])[CH2:10]3)=[CH:4][N:3]=2)[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=1
Reactant: CN1CC(Oc2ccc(Br)nc2)C1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
To a solution of 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine (0.327 g, 1.32 mmol) and 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (0.321 g, 1.58 mmol) in dioxane (5.5 mL) add Cs2CO3 (0.645 g, 1.98 mmol), xantphos (0.153 g, 0.264 mmol) and bubbled argon through reaction mixture for 15 min. Add Pd (OAc)2 (0.03 g, 0.132 mmol) in the end. The reaction was heated at 100° C. under argon for 3 h. TLC shows 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine was gone. The reaction mixture was treated with water (30 mL) and extracted with dichloromethane (3×20 mL). Organic phase was concentrated and loaded onto silica gel column separation. Using 3-5% MeOH in DCM gave 5-bromo-1-methyl-3-[5-(1-methyl-azetidin-3-yloxy)-pyridin-2-ylamino]-1H-pyridin-2-one as green solid (200 mg, 40% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.CCN(CC)CC.O>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloropropane-1-sulfonyl chloride (1.46 g, 8.22 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. is added bis-(4-methoxy-benzyl)-amine (2.22 g, 8.63 mmol) followed by Et3N (1.68 g, 10.69 mmol). After the addition, the mixture is allowed to warm to room temperature and is stirred for 2 h. The mixture is then poured into water (50 mL) and is extracted with CH2Cl2 (3×50 mL). The combined organic layers are concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 0%˜50%) to provide 3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide as colorless oil. (2.7 g, 84%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>CO.[Pd]>[ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc(N)c1
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A solution N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamide hydrochloride (0.4 g) in methanol (250 ml) was charged with a catalytic amount of 10% palladium on carbon (0.085 g). The reaction was placed under an atmosphere of hydrogen (50 psi; 3.44×105 Pa) and shaken on a Parr apparatus for 2 hours. The reaction mixture was filtered and the solvent removed in vacua. The solid product was recrystallized from 2-propanol to provide 0.18 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-amino-1-benzenesulfonamide hydrochloride as an off white crystalline solid, m.p. 110.2° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.22 (d, J=8.2 Hz, 1H ), 7.83 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.43 (t, J=5.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.95 (t, J=1.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.73 (dd, J=8.0, 1.5 Hz, 1H), 5.63 (broad s, 2H), 4.56 (t, J=7.5 Hz, 2H ), 2.96 (t, J=7.7 Hz, 2H), 2.77 (q, J=6.3 Hz, 2H ), 1.83 (m, 4H ), 1.60-1.40 (m, 4H ), 0.97 (t, J=7.3 Hz, 3H); IR (KBr) 3313, 3135, 2957, 2870, 2782, 1671, 1599, 1485, 1454, 1313, 1155, 1084, 754, 686 cm−1; MS (EI) m/e 466.2150 (466.2151 calcd for C24H30N6O2S). Anal calcd for C24H30N6O2S*HCl*0.25H2O: C, 56.79; H, 6.26; N, 16.56; Cl, 6.98. Found: C, 56.87; H, 6.22; N, 16.19; Cl, 7.22.
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.B(F)(F)F.[CH3:21][CH2:22][O:23]CC.C(OC(=O)C)(=O)C>C1COCC1>[Si:5]([O:6][CH2:7][C:8]#[C:9][C:22](=[O:23])[CH3:21])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: CCOCC
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15.1 g, 88.3%) in THF (300 mL), n-BuLi (67 mL, 105.9 mmol, 1.6 N in hexane) was added slowly at −78° C. After the addition was complete, the temperature was increased slowly to 10° C. over a period of 2 h. The reaction mixture was cooled again to −78° C. and BF3.OEt2 (14 mL, 105.9 mmol) added slowly and reaction mixture stirred at this temperature for 5 min. Acetic anhydride (11 mL, 115.6 mmol) was slowly added and the reaction was continued while temperature was allowed to rise to room temperature over a period of 2 h. After this time, reaction mass was quenched with 1N NaOH till pH 7-8 and biphasic solution was extracted with ethyl acetate. The organic layer was concentrated to obtain crude material which was further purified by column chromatography over silica gel to yield 5-((tert-butyldimethylsilyl)oxy)pent-3-yn-2-one (9.2 g, 52.6%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]([CH3:20])=[C:9]2[C:21]([O:23]CC)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.N12CCCC=C1CCCCN2.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([C:13]1[CH:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[O:1][C:21](=[O:23])[C:9]2=[C:10]([CH3:20])[NH:11][C:12]=1[CH3:19])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ncccc1O
Agent: C1=C2CCCCNN2CCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)NC(C)=C2C(=O)Oc3cccnc3C12
Temperature: 140 °C
Yield: 55.3 %

Procedure:
Diethyl 1,4-dihydro-4-(3-hydroxypyridyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (17.3 grams; 0.05 mole) was nearly dissolved in 250 ml toluene heated at 140° C. Diazabicyclo(5.4.0) undec-7-ene (8.3 grams; 8.2 ml; 0.05 mole) dissolved in 20 ml toluene was added and the reaction mixture refluxed for a period of 22 hours at 180° C. (bath temperature). The black solution was cooled and concentrated to afford 23.3 grams of a black paste. High pressure liquid chromatography (HPLC) using ethyl acetate yielded 8.3 grams of a yellow solid, m.p. 100°-150° C. Two recrystallizations from 2-propanol gave 4.5 grams (30%) of fluorescent yellow material, m.p. 150°-160° C.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]([CH3:18])=[O:17].O>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:15][C:16]([CH3:18])=[O:17])=[O:8])=[O:11]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 125 ml of ethanol were dissolved 14.2 g of sodium ethoxide, followed by the dropwise addition of a mixed liquid of 25 ml of diethyl oxalate and 13.5 ml of acetone over 20 minutes. The resulting mixture was stirred at room temperature for 3 hours. After the completion of the reaction, water was added to the reaction mixture. Ethanol was then evaporated under reduced pressure. The residue was extracted with chloroform. After the chloroform layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was then evaporated, whereby ethyl acetopyruvate (1) was obtained (O. S., Coll. Vol. 1, 238(1958)).
Reaction SMILES: [CH2:1]([C:4]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:21]1[C:22]2[C:29]([CH3:30])=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>C(Cl)Cl>[CH2:1]([C:4]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[O:11])[CH2:9][CH2:8][N:7]([C:21]2[C:22]3[C:29]([CH3:30])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 120 °C
Yield: 61 %

Procedure:
4-Allyl-N-(3-chlorophenyl)piperidine-4-carboxamide from step B (0.142 g, 0.453 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.453 mmol), N,N-diisopropylethylamine (0.236 mL, 1.35 mmol), and isopropanol (5 mL) were combined and heated at 120° C. overnight in a pressure vessel. The crude reaction was dissolved in CH2Cl2, washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (MeOH:CH2Cl2 gradient) to give the title compound in 61% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4].S(Cl)([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Cl:19])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4]
Reactant: COc1cc(CO)ccc1S(=O)(=O)N(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of OBS02014 (2.76 g, 10.55 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.15 mL, 15.82 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was redissolved and co-evaporated three times with DCM (3×20 mL) to give OBS02016 as a brown oil (2.91 g, 99%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.84; 1H-NMR (270 MHz, CDCl3)=2.96 (6H, s), 3.90 (3H, s), 4.55 (2H, s), 6.95 (1H, dd, J=1.8, 8.0), 7.01 (1H, d, J=1.8), 7.32 (1H, d, J=8.0).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:7]([OH:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].O1CCCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(OCC)(=O)C.O>[CH2:24]([O:23][C:21]([NH:1][C@@H:2]([C@@H:7]([OH:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)[C@H](C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (2S,3S)-methyl 2-amino-3-hydroxybutanoate (2.5 g, 14.73 mmol) in a 1:1 mixture of tetrahydrofuran and water (50 mL), sodium bicarbonate (1.9 g, 22.10 mmol) was added and the mixture was cooled to 0° C. and to this benzyl chloroformate (2.76 g, 16.21 mmol) was added drop wise over a period of 30 minutes. The mixture was then stirred at the room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (25 mL), organic layers were separated, washed with brine (25 mL) and dried over sodium sulfate. Removal of solvents under vacuum afforded the crude product which has been purified by silica gel column chromatography (230-400 mesh) using a gradient of ethyl acetate in pet.ether. Yield: 3.4 g (86%)1H NMR (400 MHz, DMSO-d6) δ: 1.09 (d, 3H), 3.89 (s, 3H), 3.99 (t, 1H), 4.01-4.06 (m, 1H), 5.00 (d, 1H), 5.04 (s, 2H), 7.30-7.40 (m, 5H), 7.63 (d, 1H). MS (ES) MH+: 268.1 for C13H17NO5.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CS(C)=O.O>[CH2:25]([N:28]([C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccccc23)c(C)c1
Reactant: CCCNCCC
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)c3ccccn3c12
Temperature: 130 °C
Yield: 86.8 %

Procedure:
A mixture of 4-chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido[2,3-b]indolizine (10.0 g; 30 mmol) and dipropylamine (15 mL; 1 mol) in DMSO (30 mL) is heated at 130° C. under nitrogen atmosphere for two days. The mixture is cooled to room temperature, diluted with water (ca. 300 mL), and extracted with ether (100 mL×2). The combined organics are washed successively with saturated ammonium chloride and saturated brine, dried (Na2SO4), filtered, and concentrated. The concentrate is chromatographed (first with 5% ethyl acetate in hexane and then with 10% triethylamine in hexane) to give 10.4 g of the title compound (compound 1, Table 1) as a fluorescent yellow foam (87%): 1H nmr (400 MHz, CDCl3) d 0.90 (t, 6 H), 1.6 (br, 4 H), 2.02 (s, 6 H), 2.37 (s, 3 H), 2.62 (s, 3 H), 3.2 (br, 4 H), 6.52 (t, 1 H), 6.73 (s, 1 H), 6.89 (t, 1 H), 7.00 (s, 2 H), 7.06 (d, 1 H), 8.98 (d, 1 H).