Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
As in Example 115, (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid (20 g) and 4-nitrophenol (11.2 g) in dichloromethane (250 mL) was treated with 1,3-dicyclohexylcarbodiimide (14.7 g). The mixture was stirred at 0°-5° C. for 60 minutes, then at room temperature for 3 hours. After the usual work up, the ester was crystallized from dichloromethane-hexane to yield 26.1 g of (E)-5,5-bis (3-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 129°-130° C. Recrystallization of a portion from the same solvents afforded the analytical sample, mp 129.5°-130.5° C. Anal. Calculated for C23H15F2NO4 : C, 67.81; H, 3.71; N, 3.44; F, 9.33 Found: C, 67.81; H, 3.74; N, 3.41; F, 9.37.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.CCN(CC)CC>CN(C=O)C>[N+:11]([C:5]1[C:6]([S:8][C:9]#[N:10])=[N:7][C:2]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)=[N:3][CH:4]=1)([O-:13])=[O:12]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: c1ccc2[nH]cnc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CSc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A mixture of 2-chloro-5-nitro-4-thiocyanatopyrimidine (5.0 g, 23 mmol, WO 2003/032994) and benzimidazole (2.72 g, 23 mmol) in 200 mL of DMF was cooled to 0 C and Et3N (2.33 g, 23 mmol) was added. The ice-bath was removed and the contents were stirred for 3 h at RT. The reaction mixture was diluted with water and filtered. The solid was washed with water, followed by ice-cold methanol and dried in vacuo to provide 3.1 g of 1-(5-nitro-4-thiocyanatopyrimidin-2-yl)benzimidazole. 1H NMR (300 MHz, DMSO-d6) □□ 9.70 (s, 1H), 9.15 (s, 1H), 8.90-8.80 (m, 1H), 7.95-7.80 (m, 1H), 7.55-7.35 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O1CCCC1.O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reaction time: 0.33 h

Procedure:
A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 (52.5 g, 140.7 mmol) in a mixture of tetrahydrofuran (400 mL), methanol (400 mL) and 1N aqueous sodium hydroxide (280 mL) was heated at ca 50° C. with stirring for 20 minutes. After cooling, the mixture was diluted with water (300 mL) and IN aqueous HCl (325 mL) was added. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the title acid as a cream-colored solid.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([OH:10])=[C:8]([C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14](I)[C:13]=2[CH3:23])[CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:1][C:2]([N:5]1[C:9]([OH:10])=[C:8]([C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:25][CH3:26])=[CH:29][CH:30]=3)[C:13]=2[CH3:23])[CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3O)c2C)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 1.0 g (2.2 mmol) of 1-(1,1-dimethylethyl)-5-hydroxy-4-(3-iodo-2-methyl-4-methylsulfonylbenzoyl)pyrazole, 0.541 g (3.3 mmol) of 4-ethoxyphenylboronic acid, 0.607 g (4.4 mmol) of potassium carbonate, 0.025 g (0.11 mmol) of palladium(II) acetate, 0.100 g (0.33 mmol) of tri-o-tolylphosphine, 25 mL of acetonitrile, and 3 mL of water was heated at reflux with stirring for 15 min. The resulting mixture was cooled and diluted with water. The mixture obtained was extracted with ether and acidified with concentrated aqueous hydrochloric acid. The yellow precipitate that formed was collected by filtration and recrystallized by dissolving in dichloromethane and then adding hexane to obtain 800 mg (80 percent of theory) of the title compound as a white solid melting at 110° C.
Reaction SMILES: [CH2:1]([N:8]([CH:13]=O)[CH2:9][C:10](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#C>C(OC(=O)C)(=O)C>[CH2:1]([N:8]1[CH:9]=[CH:10][C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC(=O)O)Cc1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(Cc2ccccc2)c1
Yield: 94 %

Procedure:
Using 1.93 g (10 mmol) of N-benzyl-N-formylglycine, 3.65 g (37.2 mmol) of ethyl propiolate and 10 ml of acetic anhydride, a reaction and post treatment were conducted in a similar manner as, in Referential Example 1. The resulting brown oil was purified by silica gel column chromatography [silica gel: “No.9385”, product of Merck & Co., Inc. (the same silica gel was also used in the subsequent referential examples and examples); eluent: ethyl acetate/hexane=1/3], whereby 2.156 g of the title compound were obtained (yield: 94.0%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[C:15](Cl)=[N:16][CH:17]=[CH:18][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(OCC)(=O)C>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[C:15]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:16][CH:17]=[CH:18][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc3ccnc(Cl)c3[nH]2)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3ccnc(N4CCNCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of the chloroimidazopyridine 4 (0.75 g, 2.6 mmol) and piperazine (6.8 g, 79 mmol) in DMSO (15 mL) was heated to 140° C. for 3 hours. During this time, the reaction mixture was gently swirled every 30 minutes to redissolve piperazine on the upper walls of the flask. After cooling to room temperature, ethyl acetate (150 mL) was added and the solution was washed with water (3×100 mL), dried over MgSO4, and evaporated to leave a yellow powder (0.75 g, 86%). LC/MS (method A); Rt=0.90 minutes, [M+H]+=336, purity>99%.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[C:17]4[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH2:34][CH2:33][N:32]5[C:35]([CH3:38])=[N:36][N:37]=[C:31]5[CH2:30]4)[N:24]=3)=[N:12][N:13]=2)=CC=1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[CH3:38][C:35]1[N:32]2[CH2:33][CH2:34][N:29]([C:25]3[N:24]=[C:23]([C:17]4[C:16]5[C:20](=[CH:21][CH:22]=[C:14]([C:11]6[S:10][C:9]([NH2:8])=[N:13][N:12]=6)[CH:15]=5)[NH:19][CH:18]=4)[CH:28]=[CH:27][CH:26]=3)[CH2:30][C:31]2=[N:37][N:36]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(N6CCn7c(C)nnc7C6)n5)c4c3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2n1CCN(c1cccc(-c3c[nH]c4ccc(-c5nnc(N)s5)cc34)n1)C2
Temperature: 100 °C
Yield: 2.5 %

Procedure:
A glass microwave reaction vessel was charged with N-(4-methoxybenzyl)-5-(3-(6-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (80.0 mg, 0.146 mmol) in TFA (1.0 mL). The reaction was heated in a microwave at 100° C. for 10 min, then solvent was removed. The residue was purified with RP-HPLC to give 5-(3-(6-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine 2,2,2-trifluoroacetate (2.0 mg, 2.5%) as a light yellow solid. MS (ESI, pos. ion) m/z: 430 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, br. s.), 8.80 (1H, s), 8.14 (1H, d, J=2.0 Hz), 7.61-7.72 (2H, m), 7.52 (1H, d, J=8.6 Hz), 7.22-7.43 (3H, m), 6.90 (1H, d, J=9.2 Hz), 5.07 (2H, br. s.), 4.15-4.37 (4H, m).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C@@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.C(=O)([O-])O.[Na+].ClCCl.[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([N:2]1[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C@@H:5]2[C@@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)(=[O:24])[CH3:23]
Reactant: O=C(O)[C@@H]1CC2CCCCC2CN1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1C[C@@H]2CCCC[C@@H]2C[C@H]1C(=O)O
Reaction time: 22 h
Yield: 33.4 %

Procedure:
A mixture comprising (4aR,8aS) isomer, (4aR,8aR) isomer and trans isomer of decahydroisoquinoline-3(S)-carboxylic acid was dissolved in 72 ml of water, followed by the addition of 60.9 g (725 mmol) of sodium hydrogencarbonate and 72 ml of dichloromethane at room temperature. Thereafter, 27.4 ml (290 mmol) of acetic anhydride was slowly dropwise added thereto, followed by stirring for 22 hours. Insolubles were separated by filtration. After 6N hydrochloric acid was poured thereinto to adjust to pH3, common salt was added thereto up to saturation. Extraction with chloroform was conducted and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in a reduced pressure. Dichloromethane was added thereto to thereby obtain 5.45 g of a crystal of the title compound. Yield 33.4% (two steps).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C1(=O)O[CH2:14][CH2:13][O:12]1>>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2c(c1)OCO2
Product: OCCOc1ccc2c(c1)OCO2
Yield: 99 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from sesamol (2.0 g, 14.5 mmol) and ethylene carbonate (1.0 g, 11.4 mmol): solid; yield 99%. MS m/z 182 (M)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([Cl:22])[C:18](Cl)=[N:19][CH:20]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[C:17]([Cl:22])[C:18]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[N:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
Diethyl malonate (0.87 mL, 5.7 mmol) was added dropwise to a suspension of NaH (55% in mineral oil, 0.27 g, 6.2 mmol) in DMF (6 mL) at 0° C. The ice-bath was removed and the mixture was stirred under N2 at r.t. for 20 min. 5-Bromo-2,3-dichloropyridine (1.0 g, 4.4 mmol) was added, and the mixture was stirred at 120° C. overnight. The mixture was allowed to cool and was then partitioned between water containing NaCl and EtOAc. The organic phase was dried (MgSO4) and evaporated to give a crude product which was purified by flash chromatography (25 g SiO2, heptane/EtOAc gradient) affording the title compound (0.8 g, 2 mmol, 52% yield) containing a residue of unreacted malonic ester. MS (ES+) m/z 350 [M+H]+. A part of this material was used as such in the subsequent step.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.[CH:30]1[C:35]([NH:36][C:37]([CH2:39]Cl)=[O:38])=[CH:34][CH:33]=[C:32]([F:41])[CH:31]=1>>[F:41][C:32]1[CH:31]=[CH:30][C:35]([NH:36][C:37]([CH2:39][N:18]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=3[CH3:28])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19]2(=[O:27])=[O:26])=[O:38])=[CH:34][CH:33]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CC(=O)Nc2ccc(F)cc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and alpha-chloro-4-fluoroacetanilide. 1H NMR (DMSO-d6) δ 8.06-8.03 (m, 1H), 7.70-7.62 (m, 2H), 7.51-7.46 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.17-7.13 (m, 2H), 7.02 (t, J=8.1 Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.72 (bs, 1H), 6.55 (s, 1H), 5.00 (s, 2H), 4.15 (d, J=17.4 Hz, 1H), 3.40 (d, J=17.4 Hz, 1H), 2.39 (s, 3H); MS: ESI (negative): 506 (M−H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>C(O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)N(C)C)c3)ccnc2n1

Procedure:
The product from Example 2g (177 mg, 0.86 mmol) was reacted with the product from Example 168d (249 mg, 0.86 mmol) in ethanol (5 mL) at 85° C. in a sealed tube for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (100 mg, 20.2%). 1H NMR (500 MHz, DMSO-D6) δ ppm: 8.86 (d, J=8.79 Hz, 1H) 8.52 (d, J=6.84 Hz, 1H) 7.74 (d, 1H) 7.72 (d, 1H) 7.60 (dd, J=8.79, 2.93 Hz, 1H) 7.28-7.33 (m, 1H) 7.27 (d, 2H) 7.06 (d, J=7.81 Hz, 1H) 6.99 (dd, J=8.06, 2.69 Hz, 1H) 6.71 (d, J=6.84 Hz, 1H) 2.96 (t, 2H) 2.91 (s, 3H) 2.70 (s, 3H) 1.79-1.86 (m, 2H) 0.96 (t, J=7.49 Hz, 3H); MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[C:60]([CH2:62][C:63](O)=[O:64])#[N:61]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][N:26]([C:63](=[O:64])[CH2:62][C:60]#[N:61])[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CCNCC2)CC1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.5 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (203.2 mg, 0.4843 mmol), HOAT (105.8 mg, 0.7773 mmol) and EDCI (144.5 mg, 0.7538 mmol) in DCM/DMF (4 mL/1 mL) were added N,N-diethylethanamine (209.1 mg, 2.066 mmol) and 2-cyanoacetic acid (48.1 mg, 0.565 mmol). The reaction was stirred at rt for 2.5 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a light pink solid (48.4 mg, 20.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.Cl.[CH2:12](O)[CH3:13]>>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH2:12][CH3:13])=[O:9])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(N)cn1
Temperature: 23 °C

Procedure:
A stirred suspension of 3-amino-pyridine-6-carboxylic acid (25 g) in ethanol (300 mL) at 0° C. was saturated with gaseous hydrogen chloride. The mixture was allowed to warm to 23° C. and heated to reflux for 2 hours. A clear solution was obtained. After cooling to 23° C., the mixture was concentrated in vacuo, neutralized with aqueous NaHCO3 and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO4, and concentrated in vacuo to give ethyl 3-amino-pyridine-6-carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CCN(CC)CC>C1COCC1>[C:14]([O:11][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:16])[CH3:15]
Reactant: COc1ccc(C(O)C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
4-Methoxymandelic acid (5.00 g, 27.44 mmol) was dissolved in 100 mL of THF. To this solution was added acetic anhydride (2.85 mL, 30.18 mmol), followed by Et3N (10 mL). The resulting mixture was stirred at room temperature overnight, concentrated, re-suspended in water, and extracted with EtOAc. The combined organic phase was dried over Na2SO4, and concentrated to give 5.95 g yellow syrup as the intermediate 79a. 1H NMR (300 MHz, CDCl3) δ 7.38 (d, 2H, J=8.67 Hz), 6.90 (d, 2H, J=8.67 Hz), 5.87 (s, 1H), 3.80 (s, 3H), 2.16 (s, 3H). LCMS (ESI−) [M−H]/z Calc'd 223, found 223.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[C:21]([CH3:28])[C:20]=2[F:29])[CH:17]=1)[C:13]#[N:14].CCOC(C)=O>O.C1COCC1>[NH2:25][C:24]1[C:19]([O:18][C:16]2[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=2)[C:13]#[N:14])=[C:20]([F:29])[C:21]([CH3:28])=[CH:22][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Sodium hydrosulfite (10.2 g, 58.7 mmol) dissolved in water (66 ml) was added dropwise to a vigorously stirred solution of 3-chloro-5-[(2-fluoro-3-methyl-6-nitrophenyl)oxy]benzonitrile (3.0 g, 9.78 mmol) dissolved in THF (33 mL). The reaction was stirred for 1 h then EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (2.5 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.68 (d, 1H), 7.26 (dd, 1H), 7.16 (t, 1H), 6.85 (t, 1H), 6.51 (dd, 1H), 5.17 (d, 2H), 2.06 (d, 3H) MS: m/z 277.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-fluorophenyl)quinolin-7-yl]ethanone (76 mg, 0.25 mmol) and ammonium acetate (195 mg, 2.54 mmol) in methanol (1.4 mL) and acetonitrile (1.4 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (31.9 mg, 0.507 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and then evaporated to dryness. The residue was used directly in next step (52 mg, 68%). LCMS calculated for C17H15ClFN2(M+H)+: m/z=301.1; found: 301.0.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C([Li])CCCCC.CN(C)C=O.Cl>O1CCCC1>[NH:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[CH:15]=[CH:6]1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1cnc2[nH]ccc2c1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-3-methylpyridine (Example 2a) (100 g) in anhydrous tetrahydrofuran and cooled to -15° C. was slowly added hexyllithium (2.8M, 350 ml) over 40 minutes, while maintaining the reaction temperature at -15° C. The reaction mixture was aged at -15° C. for 15 minutes and then allowed to warm to -5° C. Anhydrous dimethylformamide (40 ml) was added in one portion (temp. to 5° C.) and the resulting yellow suspension vigorously stirred at ambient temperature for 30 minutes. 5.5M Hydrochloric acid (900 ml) was added in one portion and the mixture heated at 45° C. for one hour. The mixture was cooled to 20° C. and the phases separated. The aqueous phase was covered with isopropyl acetate (500 ml), cooled to 5° C. and with vigorous stirring, neutralised by the addition of sodium hydroxide pellets (200 g, 5.0 mole). The phases were separated and the aqueous phase extracted with isopropyl acetate (500 ml). The organic phases were combined, washed with 2%w/w sodium metabisulphite (2×500 ml) and evaporated to residue (56.8 g, 91%w/w purity, 91%w/w assay yield (method 1)).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cccnc1
Temperature: 27 °C
Reaction time: 0.33 h
Yield: 66.8 %

Procedure:
To a solution of NaH (330 mg, 13.7 mmol) in DMF (10 mL) was added pyridin-3-ylmethanol (500 mg, 4.6 mmol) and the solution was stirred at 27° C. for 20 minutes. Ethyl 2-bromoacetate (921.8 mg, 5.52 mmol) was then added and the reaction mixture stirred at 27° C. for further 16 h. Once the reaction was complete by TLC analysis, the mixture was quenched by addition of water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the Ethyl 2-(pyridin-3-ylmethoxy)acetate (600 mg, 66.8%) as colorless oil which was used in next step without further purification. LCMS: 196.1 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[OH:7])=[CH:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[O:7])=[CH:2]1
Reactant: OC(c1ccsc1)c1ccsc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccsc1)c1ccsc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.1 gm (10.7 mmol) of Di-thiophen-3-yl-methanol in 50 mL of dichloromethane at room temperature was added 3.0 gm (13.9 mmol) of PCC. The reaction suspension was allowed to stir 2 hrs at room temperature. After 2 hrs, the reaction mixture was filtered and precipitates were washed with dichloromethane. The combined filtrates were concentrated. The concentrated sample was purified by flashy chromatography (hexane:ethyl acetate, from 11 to 18% ethyl acetate over 16 column volume) to obtain 1.83 gm (88.0%) of light yellow crystals; 1H NMR 500 MHz (CDCl3) δ 8.02 (d, 1H), 8.01 (d, 1H), 7.62 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 7.38 (d, 1H).