Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)=[O:11].O.ON1C2C=CC=CC=2N=N1.[C:33]1([CH2:39][CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:33]1([CH2:39][CH2:40][CH2:41][NH:42][C:17]([C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10]([N:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:11])=[CH:14][CH:15]=2)=[O:19])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCc1ccccc1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Isoindoline-2-carboxamido)benzoic acid (150 mg, 0.531 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.797 mmol) were dissolved in dimethylformamide (3 ml) followed by addition of 3-phenylpropan-1-amine (110 mg, 0.797 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (153 mg, 0.797 mmol). The homogeneous solution was stirred at ambient temperature overnight. The solution was diluted with water to give a precipitate which was filtered, washed with cold ethyl acetate then ether and dried under vacuum to provide the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.27-8.34 (bs, 1H), 7.93-7.98 (m, 1H), 7.73-7.76 (m, 2H), 7.61-7.64 (m, 2H), 7.32-7.36 (m, 2H), 7.27-7.32 (m, 2H), 7.24-7.28 (m, 2H), 7.19-7.24 (m, 2H), 7.13-7.18 (m, 1H), 4.79 (s, 4H), 3.30 (q, J=6.5 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 1.86 (p, J=7.3 Hz, 2H); MS (ESI(+)) m/e 400 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O)#[N:2].C1(P(=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:35]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCCCCCC=O
Solvent: c1ccccc1
Product: CCOC(=O)C=CCCCCCCC#N
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 14 g of 7-cyanoheptanal, 38 g of ethyl triphenylphosphoranylidene-acetate and 100 ml of benzene is refluxed for 15 hours and evaporated. The residue is triturated with diethyl ether, filtered and the filtrate evaporated. The residue is allowed to stand overnight in the refrigerator, triturated with the minimum amount of diethyl ether, the suspension filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 130°-138° /0.1 mm Hg collected, to yield the 9-cyano-2-nonenoic acid ethyl ester of the formula
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[N:47]2[CH:48]=[CH:49][N:50]=[C:46]2[CH:45]=[CH:44][CH:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:50]1[CH:49]=[CH:48][N:47]2[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)=[CH:43][CH:44]=[CH:45][C:46]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccc4nccn34)nc21
Yield: 57.8 %

Procedure:
A mixture of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (0.2 g, 0.30 mmol), 5-bromoimidazo[1,2-a]pyridine (0.066 g, 0.33 mmol), copper(I) 2-thiophene carboxylate (0.018 g, 0.09 mmol) and Pd(PPh3)4 (0.052 g, 0.045 mmol) in dioxane (5 mL) was subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 94:6) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 698 as a yellow powder (0.085 g, 58%). LCMS: RT=4.17 min, [M+H]+ 491.2. 1H NMR (CDCl3, 400 MHz) δ 9.26 (d, J=1.2 Hz, 1 H); 7.96 (dd, J=8.2, 1.2 Hz, 1 H); 7.76-7.73 (m, 2 H); 7.31 (dd, J=8.2, 5.2 Hz, 1 H); 4.38 (t, J=4.6 Hz, 4 H); 3.96 (s, 3 H); 3.89 (t, J=4.6 Hz, 4 H); 3.75 (s, 2 H); 2.96 (d, J=11.0 Hz, 2 H); 2.11 (t, J=11.0 Hz, 2 H); 1.76 (d, J=11.0 Hz, 2 H); 1.44-1.29 (m, 3 H); 1.18 (s, 6 H)
Reaction SMILES: [Si](OC1C=C2C(=CC=1)CC(C1C=CC(OC)=CC=1N)CC2)(C(C)(C)C)(C)C.Cl.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:33](Cl)=O.[Si:48]([O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][CH:61]([C:66]1[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][C:67]=1[NH:74][CH2:75][C:76]1C=CC(OCCN3CCCCC3)=C(F)C=1)[CH2:60][CH2:59]2)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>>[Si:48]([O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][CH:61]([C:66]1[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][C:67]=1[N:74]([CH2:75][CH3:76])[CH2:33][C:32]1[CH:36]=[CH:37][C:38]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:30]([F:29])[CH:31]=1)[CH2:60][CH2:59]2)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O[Si](C)(C)C(C)(C)C)ccc2C1

Procedure:
Synthesized from 2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, {2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (480 mg) was used according to an analogous synthetic method to Example 36 to provide {2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (405 mg). This compound (403 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (293 mg).
Reaction SMILES: ClCCCl.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O.C(O)(=O)C>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([Br:5])[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: Brc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
EX-595A) To a 1,2-dichloroethane (90 mL) solution of 3-bromobenzaldehyde (5.60 g, 30.3 mmol) was added 3-phenoxyaniline (5.60 g, 30.2 mmol), NaB(OAc)3H (8.26 g, 39.0 mmol) and acetic acid (1.8 mL, 31. mmol). The cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 10.49 g (98%) of the desired N-(3-phenoxyphenyl)[(3-bromophenyl)methyl]amine product as a light brown oil. 1H NMR (CDCl3) δ 4.26 (s, 2H), 6.27 (s, 1H), 6.38 (d, 2H), 7.00 (d, 2H), 7.13 (m, 2H), 7.19 (t, 1H), 7.26 (d, 1H), 7.30 (m, 2H), 7.38 (d, 1H), 7.96 (s, 1H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ ˜10) and the formation of the benzyl peak (δ 4.26) in the 1H NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[Br:24][CH2:25][CH2:26][CH2:27]Br.ClCCCCCCOC1C(OC)=CC=C2C=1NC(=O)C=C2NC1C(Cl)=CN=CC=1Cl>>[Br:24][CH2:25][CH2:26][CH2:27][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: BrCCCBr
Agent: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCBr

Procedure:
8-(3-Bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3) and 1,3-dibromopropane following the procedure outlined for Intermediate 4 (modifications: 1.0 equiv KHMDS and 5.0 equiv of dibromide used; reaction run at room temperature). MS (ESI): 472.1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH:12]1([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (5.2 mL, 36.4 mmol) was added dropwise to an ice-cold solution of cyclobutylamine (2 g, 28.1 mmol) in dichloromethane (20 mL), with stirring. Triethylamine (4.7 mL, 33.7 mmol) was added dropwise to the ice-cold solution, and once the addition was complete the reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was washed with saturated sodium bicarbonate solution (×2), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane as eluant to afford the title compound, 3.72 g. 1H NMR (CDCl3, 300 MHz) δ: 1.68 (m, 2H), 1.82 (m, 2H), 2.35 (m, 2H), 4.19 (m, 1H), 4.92 (m, 1H), 5.14 (s, 2H), 7.25-7.39 (m, 5H). MS TSP+ m/z 223.2 [MH]+
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.N1C=CN=C1.[C:35]([Si:39]([CH3:42])([CH3:41])Cl)([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[Si:39]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41]
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reaction time: 0.67 h
Yield: 80 %

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 10 ml of DMF, then imidazole (0.68 g, 10 mmol) and tert-butyl dimethyl chlorosilane (1.5 g, 10 mmol) were added with stirring. The whole system was reacted at a temperature ranging from 20° C. to 25° C. for 40 min. After the reaction was complete, water was added to the system and the resultant mixture was extracted with diethyl ether for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid of 4.0 g. Yield: 80%. Melting point: 107.7-109.3° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.[CH2:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CCN1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCN1CCN(c2ccc(C(=O)OC)cc2)CC1

Procedure:
4-Fluorobenzoic acid methyl ester (53 mmol), 1-ethyl-piperazine (44 mmol) and potassium carbonate (44 mmol) are suspended in dimethyl-acetamide (50 ml) and stirred under reflux overnight. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A brownish powder with mp. 102-104° C., Rf=0.22 (CH2Cl2MeOH=95:5) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH2:19])[CH2:8][CH2:7]1)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH:19][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ccc(Cl)cc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of 0.710 g (2.39 mmol) of [1-(2-amino-4-chloro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester in acetonitrile (25 mL) is added 0.37 mL (2.9 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue is treated with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.590 g (56.7%) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[S:15]1)=[O:11]
Reactant: Oc1nsc(OC2CCCCC2)n1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)n1sc(OC2CCCCC2)nc1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1 ml of triethylamine and 6.7 g of methyl isocyanate were added to a solution of 14.01 g of 3-hydroxy-5-cyclohexyloxy-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and the mixture was stirred for 2 hours at 20° C, treated with activated carbon, stirred and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in isopropyl ether. The mixture was vacuum filtered and the recovered crystals were dried to obtain 13.5 g of 2-(N-methylcarbamoyl)-5-cyclohexyloxy-1,2,4-thiadiazole-3-one melting at 121° C.
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=4[Cl:68])[C:62](O)=[O:63])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1>C1COCC1.O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([C:62]([N:5]5[CH2:6][C:3]([F:7])([F:2])[CH2:4]5)=[O:63])[CH:65]=[CH:66][C:67]=4[Cl:68])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)N2CC(F)(F)C2)ccc1Cl
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a mixture of 3,3-difluoroazetidine hydrochloride (1.18 g, 9.13 mmol), DIPEA (5 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3.00 g, 6.09 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 5 h, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo to give 8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (3.2 g, yield 93%). 1H NMR (DMSO, 400 MHz): δ7.56-6.59 (m, 7H, ArH), 4.76-4.48 (m, 4H, 2CH2), 4.31 (t, J=5.2 Hz, 2H, CH2), 3.33 (s, 3H, CH3), 2.96 (t, J=5.2 Hz, 2H, CH2)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)=O)=CC=1.O>CC#N.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Reactant: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)OCCN1c2nc(Cl)cc(=O)n2CC1(C)C
Temperature: 65 °C
Yield: 59.4 %

Procedure:
To 0.200 g of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one suspended in 7 mL of CH3CN, 0.65 g of cesium carbonate and 0.51 g of 2-isopropoxyethyl 4-methylbenzenesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1). 0.17 g (yield=45%) of 7-chloro-1-(2-isopropoxyethyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a brown powder.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)C.I([O-])(=O)(=O)=[O:26].[Na+]>CC(C)=O.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1)(=[O:26])[CH3:1]
Reactant: C=C(C)c1cc(-c2coc(CCC(=O)OC)n2)cc(C(F)(F)F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CCc1nc(-c2cc(C(C)=O)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a stirred solution of methyl 3-(4-(3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 49, 0.175 g, 0.516 mmol), and osmium tetroxide solution (0.21 g, 4 wt % in water, 0.033 mmol) in acetone (10.0 mL) and water (3.0 mL) was added sodium periodate (0.331 g, 1.55 mmol) at room temperature and the mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-acetyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.128 g, 73%) as a white solid: ESI MS m/z 342 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1.CC(C)([O-])C.[K+]>CC(O)(C)C.O>[CH:30]([C:26]1[N:25]=[C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([O:42][CH2:41][CH2:40][N:37]6[CH2:38][CH2:39][O:34][CH2:35][CH2:36]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:33])=[N:17]2)[CH:29]=[CH:28][CH:27]=1)([CH3:31])[CH3:32]
Reactant: OCCN1CCOCC1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCOCC5)ccn34)c12
Temperature: 95 °C
Yield: 52.7 %

Procedure:
7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.250 g, 0.565 mmol), 2-morpholinoethanol (0.371 g, 2.82 mmol), and potassium t-butoxide were combined in t-BuOH in a reaction tube. The tube was sealed and heated to 95° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were with 10% aqueous potassium carbonate, dried over sodium sulfate, and concentrated. The resulting crude product was triturated with ether to give 165 mg (53%) of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide as a tan solid. MS (APCI), positive scan, m/z=554.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21

Procedure:
16 g (55.6 mmol) of ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylate and 50 ml of ethyl alcohol were introduced into a round-bottomed flask. A solution of 2.5 g (58.5 mmol) of sodium hydroxide in 50 ml of water was added and the mixture was heated at reflux for one hour. The reaction medium was evaporated to dryness, taken up in water and ethyl ether, the aqueous phase decanted off, acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. 14 g (97%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid were recovered in the form of a colorless oil.