Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=O.[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:36][CH2:35][CH2:34][CH2:33][NH:32][C:31](=[O:37])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:25])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
Compound 27gg, N-[3-{7-(N,N-Diethylamino)coumarin-3-carboxylamido}butyl]-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide was synthesized by the method depicted in FIG. 8. Briefly, indomethacin was complexed with tert-Butyl-3-aminopropylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). tert-Butyl 3-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]propylcarbamate was produced as a pale yellow solid at 70% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(4-qminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with triethylamine (TEA) in dimethyl sulfoxide (DMSO) for 5 minutes at room temperature prior to the addition of 7-(N,N-Diethylamino)coumarin-3-carboxylic acid succinimidyl ester. The reaction proceeded for 16 hours at room temperature and produced Compound 27gg as a yellow solid (66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.CCN(CC)CC.[Cl:38][CH:39]([CH2:43]Cl)[C:40](Cl)=[O:41]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[C:39]([Cl:38])=[CH2:43])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: O=C(Cl)C(Cl)CCl
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(Cl)C(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 463 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.28 mL (2.0 mmol) of Et3N in 8 mL of THF was added 0.131 mL (1.2 mmol) of 2,3-dichloropropanoyl chloride. The solution was stirred 0.5 h, warming to ambient temperature. The solution was quenched with water and filtered. The solid was washed with 0.1 N aq. HCl, then water, then 1:1 hexanes-ether. The product was air-dried briefly to afford 390 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-chloroacrylamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1H NMR (300 MHz, DMSO) δ 12.49(br. s, 1H); 10.14(br. s, 1H); 7.97(s, 2H); 7.53(d, 2H, J=8.4 Hz); 7.22(d, 2H, J=8.4 Hz); 6.36(d, 1H, J=2.6 Hz); 6.03(d, 1H, J=2.5 Hz); 3.82(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)[C:21]=1[C:22](O)=[O:23].CCN(C(C)C)C(C)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)[C:21]=1[C:22]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:23]
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1c(F)cccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 1.09 g, 3.87 mmol) in DCM (13 ml) was added 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1186050-58-7; 0.802 g, 3.87 mmol), DIPEA (2.027 ml, 11.61 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.579 g, 4.26 mmol) and EDC (0.816 g, 4.26 mmol). The reaction was stirred at room temperature for 17 hours and was then partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic fit and concentrated in vacuo. The residue was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) and recrystallised from IPA to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(SC)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reaction time: 48 h
Yield: 70.7 %

Procedure:
To a stirred solution of ethyl 6-chloro-8-(methylthio)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Step 3, 0.203 g, 0.575 mmol) in THF:EtOH:H2O (7:2:1, 5 mL), was added aqueous sodium hydroxide (0.63 mmol, 0.25 mL of 2.5 N soln.) and allowed to stir for two days. The resulting clear, yellow solution was concentrated in vacuo, was diluted with water (35 mL), and was acidified with concentrated HCl resulting in formation of a yellow suspension. Vacuum filtration of the suspension yielded the title compound as a yellow powder (0.132 g, 71%). 1HNMR (acetone-d6/300 MHz) 7.87 (s, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H), 5.93 (q, 1H, J=7.05 Hz), 2.53 (s, 3H). LRMS m/z 323 (M−H); ESHRMS m/z 322.9782 (M−H, C12H7F3O3ClS, Calc'd 322.9757). Anal. Calc'd for C12H8F3O3ClS: C, 44.39; H, 2.48. Found: C, 44.63; H, 2.52.)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:33]([C:34](=[O:45])[NH:35][C:36]3[CH:44]=[C:43]4[C:39]([CH:40]=[N:41][NH:42]4)=[CH:38][CH:37]=3)=[CH:32][C:17]3[N:18]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1.CCOCC>[NH:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([NH:35][C:34]([C:33]3[C:14]([N:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]([F:30])([F:31])[F:29])=[N:18][C:17]=4[CH:32]=3)=[O:45])[CH:44]=2)[CH:40]=[N:41]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of {1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.25 mmol; see Example 155) in methanol (1 mL) was 4M HCl in dioxane (0.5 mL) added. The resulting mixture was stirred at room temperature for 5-6 h. The volatiles were removed in vacuo, and the residue obtained was suspended in ether. The solid obtained was collected by filtration, washed with ether and dried in vacuo to afford 6-(4-Amino-piperidin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 535 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[CH3:27][C:28]1[CH:29]=[N:30][N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C@H:38]([N:42]2[CH2:45][C:44]4([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[CH2:43]2)[CH2:37][CH2:36]3)[CH:32]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:48]2[CH2:49][CH2:50][C:44]3([CH2:43][N:42]([C@H:38]4[C:39]5[C:35](=[CH:34][C:33]([N:31]6[CH:32]=[C:28]([CH3:27])[CH:29]=[N:30]6)=[CH:41][CH:40]=5)[CH2:36][CH2:37]4)[CH2:45]3)[CH2:46][CH2:47]2)=[O:12])=[N:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)nc1
Reactant: Cc1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-n5cc(C)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 25.9 mg, 0.16 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (25.9 mg, 0.16 mmol) and the reaction was stirred overnight at room temperature. In a separate flask, to a mixture of 2-((R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride (8-1b, 60.0 mg, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (0.31 mL, 0.23 mmol). The activated acid was then added to the amine solution and the resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated and purified on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) 12 g silica column eluting with 50-100% MeOH in ethyl acetate gradient to give 26 mg (36%) of the title compound (8A) as a gum. MS (ES+) 472.9 (M+H)+. 1H NMR (CD3OD) δ 1.62-1.75 (m, 4H), 1.85-1.97 (m, 1H), 2.13 (s, 3H), 2.17-2.31 (m, 1H), 2.80-2.92 (m, 1H), 3.03-3.15 (m, 1H), 3.20-3.27 (m, 2H), 3.32 (d, 2H), 3.48-3.56 (m, 4H), 3.84 (s, 3H), 3.85 (s, 2H), 4.03 (dd, 1H), 7.22-7.28 (m, 1H), 7.35 (dd, 1H), 7.38-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.55 (s, 1H), 7.94 (s, 1H), 8.13 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14]C)=[O:13])=[N:11][C:4]=2[NH:3]1.O.[OH-].[Na+]>O1CCOCC1>[O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[N:11][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(n1)NC(=O)CS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CSc2ccc(C(=O)O)nc2N1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (788 mg) in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 h with 0.5M NaOH solution (8 mL) and stirred overnight. After evaporation to approx. 3 ml, water (5 mL) was added and 2M HCl to pH4. The precipitated solid was filtered off, washed with a small volume of water and dried under vacuum to give a solid (636 mg); LC/MS (APCI−) m/z 209 ([M−H]−, 5%), 165([M-COOH]−, 100%).
Reaction SMILES: [Mg].II.Br[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][Si:14](OCC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>C(OCC)C.CCCCCCC>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][SiH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)=[CH2:5]
Reactant: CCO[Si](C)(OCC)OCC
Reactant: BrC=Cc1ccccc1
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: II
Agent: [Mg]
Solvent: CCCCCCC
Solvent: CCOCC
Product: C=Cc1ccc(C[SiH](OCC)OCC)cc1
Temperature: 2 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
In a three-neck flask under argon and while being stirred mechanically, 11.7 g (480 mmol) of magnesium chips and some iodine crystals in 40 ml of a solution A (55% diethyl ether, 45% tetrahydrofuran) are mixed together. Then, a solution of 80.0 g (436 mmol) of bromostyrene, dissolved in 210 ml of solvent mixture A, is slowly added in drops, and thus a continuous exothermic reaction is achieved. The solution is stirred under reflux. After the end of the exothermic reaction, the reaction mixture is cooled to 2° C., and then 155.5 g (872 mmol) of methyltriethoxysilane in 160 ml of dry diethyl ether is added; the temperature must not exceed 15° C. After the end of the substitution reaction, stirring is continued at room temperature overnight. Approximately 200 ml of n-heptane is then added, thus the magnesium salts precipitate. The latter are filtered off, 9.7·10−2 g (0.44 mmol) of 2,5-di-tert-butylhydroquinone is added to the filtrate, the solvent is drawn off in a rotary evaporator, and the residue is distilled in fractionated form under vacuum. 72.5 g (307 mmol) of the product was obtained with a yield: 70.3%, and a boiling point of 65-66° C. (0.05 mbar)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=O)=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4].[CH3:16][NH:17][CH3:18].CO>>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:17]([CH3:18])[CH3:16])=[O:14])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Reactant: CNC
Solvent: CO
Product: CC(O)C(O)c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A mixture of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (52.0 mg, 0.25 mmol) and a 2.0M solution of dimethylamine in methanol (Aldrich, 15.0 ml, 30.0 mmol) was stirred and heated at a bath temperature of 100° C. in a microreactor for four nights. After cooling, the reaction mixture was concentrated in vacuo. The residue (60.3 mg) was purified by preparative TLC [Merck Kieselgel 60, Art 1.05744, 0.5 mm thick, ×2; development: CH2Cl2 - MeOH (8:1); elution: CH2Cl2 - MOH (3:1), 240 ml]. The recovered white solid residue was suspended in THF, and the mixture was filtered through a short pad of Celite. The filter cake was washed with THF. The combined filtrate and washings were concentrated in vacuo to give 5-(1,2-dihydroxypropyl)-N,N-dimethyl-2-pyridinecarboxamide as a white solid (45.2 mg, 80.6%): 1H-NMR (270 MHz) δ(CDCl3): 8.41 (d, J=1.8 Hz, 1 H), 7.76 (dd, J=7.9, 1.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1 H), 4.86 (d, J=3.7 Hz, 1 H), 4.11˜3.97 (m, 1 H), 3.80 (br.s, 1H), 3.13 (s, 3H), 3.04 (s, 3H), 2.68 (br.s, 1H), 1.15 (d, J=6.6 Hz, 3H) ppm; MS m/z: 225 (7.9%, M++1), 224 (50.9%, M+), 153 (100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.P(OC)(OC)OC.C(O[K])(C)(C)C.[CH:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]#[N:38])=[CH:34][CH:35]=2)[NH:30][N:29]=1)=O.Cl>CN(C=O)C.O>[C:37]([C:33]1[CH:32]=[C:31]2[C:36]([C:28](/[CH:26]=[CH:2]/[C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)=[N:29][NH:30]2)=[CH:35][CH:34]=1)#[N:38]
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)O[K]
Agent: COP(OC)OC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C#N)ccc23)cc1
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (4.58 g, 20 mmol) and trimethyl phosphite (3.54 mL, 30 mmol) was refluxed (oil temp. 125° C.) for 1 h under argon. After cooling to rt, the reaction mixture was diluted with DMF (50 mL) and cooled to 0° C. using ice bath. tBuOK (3.92 g, 35 mmol) was added slowly. After addition, the resulting dark brown solution was stirred for 5 min at 0° C. before a solution of 3-formyl-1H-indazole-6-carbonitrile (2.0 g, 11.7 mmol) in DMF (15 mL) was added dropwise via a pasteur pipette over 5 min. The reaction mixture was then stirred for 90 min at 0° C.; 2N HCl (25 mL) was added slowly over 2 min, followed by H2O (100 mL). The resulting suspension was stirred for 5 min at 0° C. The precipiates collected by suction filtration were rinsed well with H2O and dried to give crude (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (3.70 g) as an orange solid. Trituration with 50 mL of ether, followed by sonication and suction filtration gave pure (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (2.56 g, 72%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.76 (d, J=16.4 Hz, 1H), 7.63 (d, J=16.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 3.86 (s, 3H); MS ESI 304.1 [M+H]+, calcd for [C18H13N3O2+H]+ 304.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:16])=[O:8])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ncccc1C(=O)O
Product: COC(=O)c1ncccc1C(=O)Cl

Procedure:
A mixture of 2-methoxycarbonylnicotinic acid (4.0 g) and thionyl chloride (30 ml) is heated under reflux until homogeneous. The remaining thionyl chloride is distilled off in vacuo to give 2-methoxycarbonylnicotinoyl chloride.
Reaction SMILES: [C:1]([O:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])(=O)[C:2]([CH3:4])=C.[CH2:12]([O:15][C:16]1C=CC(O)=[CH:18][CH:17]=1)[CH:13]=[CH2:14].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:7]([O:6][C:1]1[CH:2]=[CH:4][C:12]([O:15][CH2:16][CH:17]=[CH2:18])=[CH:13][CH:14]=1)(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=CCOc1ccc(O)cc1
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(OC(=O)C(=C)C)cc1
Temperature: 37 °C
Yield: 84.5 %

Procedure:
Methacrylic anhydride (6.92 g; 0.045 moles) was added dropwise to a chilled solution of purified 4-allyloxyphenol (7.0 g; 0.047 moles), triethylamine (3.55 g; 0.035 moles), 4-dimethylaminopyridine (0.43 g; 0.004 moles), 2-6-di-tert-butyl-4-methylphenol (0.018 g; 0.08 m moles) and toluene (20 ml) in a stirred 100 ml reaction flask fitted with a reflux condenser, magnetic stirrer and thermocouple probe. During the addition the reaction temperature increased to 37° C. The mixture was heated at 110° C. for 1.5 hour, cooled and washed sequentially with equal volumes of saturated sodium bicarbonate, dilute hydrochloric acid and water. The solution was dried over magnesium sulfate and the solvent removed under reduced pressure to yield 4-allyloxyphenyl methacrylate (8.3 g; 90% yield) as a clear yellow liquid. The structure of the monomer was confirmed by proton and infrared spectral analysis and GC analysis indicated a purity of 90%.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=1)[CH:2]=C.C[N+]1([O-])CC[O:30]CC1.O1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O>[O:30]=[CH:2][CH2:1][C:4]1[C:12]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=1
Reactant: C=CCc1cn(S(=O)(=O)c2ccccc2)c2cccc(C(=O)OC)c12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1c(CC=O)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
To a 0° C. cooled solution of methyl 3-allyl-1-(phenylsulfonyl)-1H-indole-4-carboxylate (4.80 g, 13.50 mmol) from Step B above and N-methylmorpholine-N-oxide (2.82 g, 24.31 mmol) in a 3:1 mixture of tetrahydrofuran/water (50 mL) was added OsO4 (4 wt % in water, 5.0 mL, 54.0 mmol). The resulting mixture stirred at room temperature for 24 h, then was diluted with a saturated aqueous solution of Na2S2O5 (200 mL). The tetrahydrofuran was removed under reduced pressure and the mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was dissolved in a 3:1 mixture of tetrahydrofuran:water (50 mL), to which sodium periodate (11.55 g, 54.0 mmol) was added. The mixture stirred at room temperature for an additional 24 h. The tetrahydrofuran was removed under reduced pressure and the mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-(2-oxoethyl)-1-(phenylsulfonyl)-1H-indole-4-carboxylate (2.50 g, 45%) as a crude yellow oil, which was directly elaborated without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=C(C#N)[CH:8]=2)[CH:2]=1.[OH-:18].[K+].C.[CH2:21]([OH:24])[CH2:22]O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[C:22]([C:21]([OH:24])=[O:18])[CH:8]=2)[CH:2]=1
Reactant: OCCO
Reactant: N#Cc1cc(-c2cccnc2)n2c1CCCC2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(-c2cccnc2)n2c1CCCC2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile (15.6 g) and of potassium hydroxide powder (15.8 g) in ethylene glycol (150 cc) is heated at a temperature of about 156° C. for 11 hours and 30 minutes. After 16 hours' stirring at a temperature of about 20° C., the solvent is evaporated off under reduced pressure (2 mm Hg; 0.27 kPa) at a temperature of about 100° C. The residue obtained is dissolved in distilled water (250 cc). The solution obtained is treated with decolourising charcoal (0.5 g) and filtered. The filtrate is adjusted to a pH of about 5 at a temperature of about 25° C. by addition of a 5 N aqueous solution of hydrochloric acid (50 cc). The suspension obtained is stirred at a temperature of about 20° C. for 1 hour. The crystals are separated off by filtration, washed 5 times with distilled water (250 cc in total) and then dried in air. 3-(3-Pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid (13.4 g) is thus obtained in the form of beige crystals melting at 198° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:21])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN2CCC1CC2
Reactant: O=C=Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
To a solution of quinuclidin-3-ol (635 mg, 5.00 mmol) in THF (15 mL) was added NaH [60% dispersion in mineral oil](260 mg, 6.50 mmol) at room temperature. The mixture was stirred for 15 min and 3-bromophenyl isocyanate (990 mg, 5.00 mmol) was added under stirring. The resulting mixture was stirred at room temperature for 18 h, quenched with brine and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (eluting with EtOAc/methanol 3:1) to give quinuclidin-3-yl 3-bromophenylcarbamate as a white solid (0.70 g, 43%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17](OC)=[O:18])(=O)[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:16]1[CH:17]([OH:18])[N:10]2[N:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]2[NH:12][C:13]=1[CH3:14]
Reactant: Nc1[nH]ncc1-c1ccccc1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)CC1=C(C)Nc2c(-c3ccccc3)cnn2C1O
Yield: 79.8 %

Procedure:
To a solution of 4-phenyl-1H-pyrazol-5-amine (0.5 g, 3.14 mmol) and dimethyl 2-acetylsuccinate (1.77 g, 9.4 mmol) in xylene (100 mL) was added p-toluenesulfonic acid monohydrate (5 mg, 0.263 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 20 hrs. The solid was filtered and washed by hexanes to afford (0.75 g, 80%) of the title compound. 1H-NMR (500 MHz, DMSO-d6) δ ppm 2.38 (3H, s), 3.39 (2H, s), 3.59 (3H, s), 7.33 (1H, S), 7.47 (2H, m), 7.57 (2H, m) 8.13 (1H, S), 11.87 (1H, s).