Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][CH:5]([C:10](=O)[CH3:11])[C:6](OC)=[O:7].C(OC)(=O)[NH:32][NH2:33].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][C:5]1[C:6]([OH:7])=[N:32][NH:33][C:10]=1[CH3:11]
Reactant: COC(=O)NN
Reactant: COC(=O)C(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 99.1 %

Procedure:
3.09 g of methyl 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-oxobutyrate and 1.23 g of methyl carbazate were suspended in 30 ml of toluene, and the mixture was heated under reflux for 5 hours. The solution was cooled to room temperature, then, the reaction solution was poured into ice water and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with a mixed solvent of n-hexane:ethyl acetate (3:1) to obtain 2.94 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O-])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([Cl:2])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
PCl5 (0.44 mol, 89.2 g) was added to p-toluenesulfonic acid sodium salt (0.4 mmol, 77.6 g). After mixed completely, the mixture was heated to 80° C. in water bath and stirred for 2 h, then cooled to room temperature. The reaction was quenched by pouring onto 600 mL of water and ice. The mixture was filtered and gives the product as white solid. (69.8 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH2:11]([S:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:30]([OH:40])[CH:29]=2)=[CH:21][C:20]=1[O:41][CH3:42])(=[O:17])=[O:16])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH2:11]([S:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:30]([O:40][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:29]=2)=[CH:21][C:20]=1[O:41][CH3:42])(=[O:17])=[O:16])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(O)c2)cc1OC
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(OCc3cccc(OC)c3)c2)cc1OC
Temperature: 70 °C
Yield: 41 %

Procedure:
68 μl (0.5 mmol) of 3-methoxybenzyl chloride are added to a solution of 200 mg (0.5 mmol) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-hydroxyphenyl)propanoate and 89 mg (0.5 mmol) of potassium carbonate in 5 ml of methyl ethyl ketone, and the reaction medium is then heated at 70° C. for 48 hours. After cooling, water is added and the reaction medium is then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 120 mg (48%) of methyl 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-(3-methoxybenzyloxy)phenyl]propanoate are obtained.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.Cl.Cl.[OH:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([C@@H:63]2[CH2:67][C@H:66]([SH:68])[CH2:65][NH:64]2)[CH2:59][CH2:58]1>C(#N)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:68][C@@H:66]3[CH2:65][NH:64][C@H:63]([CH:60]4[CH2:59][CH2:58][N:57]([CH2:56][CH2:55][OH:54])[CH2:62][CH2:61]4)[CH2:67]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: OCCN1CCC([C@@H]2C[C@H](S)CN2)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C4CCN(CCO)CC4)C3)[C@H](C)[C@H]12
Reaction time: 19 h
Yield: 55.3 %

Procedure:
To a solution of p-nitrobenzyl (1R, 5S, 6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (8.92 g, 15 mmol) in acetonitrile (600 ml), N,N-diisopropylethylamine (10.7 ml, 61.5 mmol) was added under cooling with ice and (2S, 4S)-2-[N-(2-hydroxyethyl)piperidin-4-yl]-4-mercaptopyrrolidine dihydrochloride (4.80 g, 15.8 mmol) was further added in limited amount. After the mixture was stirred at the same temperature for 19 hours, the reaction solution was concentrated to a volume of 300 ml and stirred under cooling with ice for 2 hours. Precipitates were collected by filtration and washed with acetonitrile, followed by drying to obtain p-nitrobenzyl (1R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-2-[(2S, 4S)-2-[N-(2-hydroxyethyl)piperidin-4-yl]pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (4.77g, yield: 55.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1>CO.Cl.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(F)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of 5-fluoro-pyridine-2-carbonitrile (0.16 g, 1.27 mmol) and Pd/C (0.030 g, 10% wt) in 15 ml of MeOH and 0.50 ml of concentrated HCl was placed under H2 which was provided by a balloon and stirred at RT for 4 h, filtered through Celite®, condensed, the residue was purified by flash column chromatography. The titled compound was obtained as a light yellowish solid. MS (ES+): 127.2 (free base)(M+H)+. Calc'd for C6H7FN2 (free base)—126.13.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[C:14]([CH3:15])=[N:13][S:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[N:23]=[C:22]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O>[CH3:15][C:14]1[C:10](/[C:3](=[N:2]\[O:1][CH2:17][C:18]2[N:23]=[C:22]([N:24]3[C:25](=[O:34])[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:32]3=[O:33])[CH:21]=[CH:20][CH:19]=2)/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][S:12][N:13]=1
Reactant: Cc1nsnc1C(=NO)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: Cc1nsnc1/C(=N\OCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82 %

Procedure:
To a stirred solution of N-hydroxy-1-(4-methyl-1,2,5-thiadiazol-3-yl)-1-phenylmethanimine (24.3 g, 111 mmol) in dry acetonitrile (600 mL) were added 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (36.9 g, 116 mmol), cesium carbonate (37.9 g, 116 mmol) and potassium iodide (1.84 g, 11 mmol). The reaction mixture was stirred at room temperature for 14 h, then diluted with water (200 mL) and concentrated in vacuo. The residue was extracted with ethyl acetate (2×300 mL). The combined organic layers were combined and concentrated in vacuo to afford 2-{6-[({[(Z)-(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione as a red oil [49 g, yield 82%; HPLC/MS: m/z=456 (M+H); log P(HCOOH)=3.99].
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:4]1[C:5]([O:7]C)=O)[CH3:2].[OH-].[Na+].Cl.ON1C2C=CC=CC=2N=N1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH2:35].Cl.CN(C)CCCN=C=NCC>CO.CCOCC>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH:35][C:5](=[O:7])[C@@H:4]1[CH2:9][CH2:10][C:11](=[O:12])[N:3]1[CH2:1][CH3:2]
Reactant: NCc1ccc(F)cc1Cl
Reactant: CCN1C(=O)CC[C@H]1C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOCC
Product: CCN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.4 %

Procedure:
Methyl 1-ethyl-5-oxo-prolinate (0.135 g, 0.79 mmol, prepared as described below) was dissolved in methanol (4 ml) and treated with 2M aqueous sodium hydroxide (0.592 ml, 1.18 mmol). The mixture was stirred for ˜4 hrs at room temperature and then evaporated to give a residue which was then treated with an excess of 1M hydrogen chloride in ether (˜5 ml) for 10 minutes. The mixture was evaporated once more and the residue was dissolved in dichloromethane (4 ml) and dimethylformamide (2 ml) and filtered to remove solids. The resulting solution was transferred to a reaction tube and 1-hydroxybenzotriazole (0.117 g, 0.87 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.138 g, 0.87 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.167 g, 0.87 mmol) were then added. The mixture was flushed with argon and then stirred at room temperature over the weekend. The mixture was then diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-prolinamide (0.086 g) as a white solid. LC/MS [M+H]+=299.1, retention time=2.13 minutes.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:17])[CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:17])[CH2:15][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2C(=O)CCl)C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2C(=O)CN2CCC(c3noc4cc(F)ccc34)CC2)C1
Yield: 53.7 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-3-chloroacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.95 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.9 g of 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-oxoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 92°-94° C. as 3/2oxalate 1/2 hydrate thereof.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1

Procedure:
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Butyl-4-[4(3-methyl-butoxy)-benzenesulfonyl]-piperidine4-carboxylic ethyl ester (4.4 g, 10 mmol) dissolved in TBF:methanol (3:1 150 ml) and IO N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.2 g (77%); white solid; mp 188° C.; MS: 412 (M+H)+
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH2:14][CH3:15])[S:5]([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6])[CH:2]=[CH2:3].C(OOC(C)(C)C)(C)(C)C.[CH2:26]([O:28][P:29]([O-:33])[O:30][CH2:31][CH3:32])[CH3:27]>>[CH2:12]([N:4]([CH2:1][CH2:2][CH2:3][P:29]([O:30][CH2:31][CH3:32])(=[O:33])[O:28][CH2:26][CH3:27])[S:5]([C:8]([F:11])([F:9])[F:10])(=[O:7])=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: C=CCN(CCCC)S(=O)(=O)C(F)(F)F
Reactant: CCOP([O-])OCC
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCN(CCCP(=O)(OCC)OCC)S(=O)(=O)C(F)(F)F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Over a 60 minute period, a solution of the above-prepared N-allylsulfonamide (24.60 g, 0.10 mole) and diethylphosphite (15 g) was added dropwise concurrently with a solution of di-t-butyl peroxide (0.90 g) in diethylphosphite (5 g) to diethylphosphite (80 g) being stirred at 150° C. with an argon purge. The resulting mixture was stirred for an additional 1 hour under these conditions. The excess diethylphosphite was distilled at 10-20 torr and the residue fractionally distilled to give 19.64 g (b.p. 150°-153° C. at 0.20 torr) of the desired compound, diethyl 3-(N-butyltrifluoromethanesulfonamido)propanephosphonate. A mixture of the phosphonate prepared above (15.36 g, 0.040 mole) and bromotrimethylsilane (13.46 g. 0.088 mole) was stirred under a reflux condensor and calcium chloride drying tube for 96 hours. Then water (75 ml) was added and the resulting mixture stirred for 15 minutes followed by extraction with three 50 ml portions of diethylether. The ether portions were combined, dried with MgSO4 and evaporated in vacuo to give 12.25 g of the desired compound, 3-(N-butyltrifluoromethanesulfonamido)propanephosphonic acid.
Reaction SMILES: [CH:1]1([C@@H:4]2[O:25][CH2:24][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:8]=[C:9]([NH:15]C(=O)C4C=CC=CC=4)[S:10][C@H:11]([CH2:12][O:13][CH3:14])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.FC1C=C(F)C=CC=1[C@]12CO[C@@H](C3CCO3)C[C@H]1CSC(N)=N2.[ClH:57]>ClCCl.C(OCC)C>[ClH:57].[CH:1]1([C@@H:4]2[O:25][CH2:24][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:8]=[C:9]([NH2:15])[S:10][C@H:11]([CH2:12][O:13][CH3:14])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: COC[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Agent: Cl
Agent: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CCO3)C[C@H]2CS1
Solvent: ClCCl
Solvent: CCOCC
Product: COC[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
Conversion of rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C42) to the free base of the product was carried out via the method described for synthesis of (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (4) in Example 4. In this case, purification was effected using silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane), affording an oil. This was dissolved in dichloromethane and treated with a 1 M solution of hydrogen chloride in diethyl ether; removal of volatiles under reduced pressure provided the product as a solid. Yield: 8.6 mg, 21 μmol, 58%. LCMS m/z 369.2 [M+H+]. 1H NMR, free base of 5: (400 MHz, CDCl3) δ 7.33 (ddd, J=9.0, 9.0, 6.6 Hz, 1H), 6.74-6.87 (m, 2H), 4.03 (dd, J=10.9, 2.3 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.58-3.65 (m, 1H), 3.32-3.39 (m, 2H), 3.30 (s, 3H), 2.79-2.87 (m, 2H), 1.63-1.74 (m, 1H), 1.50-1.57 (m, 1H), 0.91-1.04 (m, 1H), 0.47-0.61 (m, 2H), 0.38-0.46 (m, 1H), 0.19-0.27 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:18]([C:24](=O)[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.C(OC(C)C)(C)C>C1(C)C=CC=CC=1.O>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:24]([CH3:25])[N:16]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1cnc(N)c(OCC2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCC3CCCCC3)cc(C)cn12
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a solution of 1.38 g of 3-(cyclohexylmethoxy)-5-methylpyridin-2-amine in 24 ml of toluene were added 1.21 ml of ethyl 2-chloro-3-oxobutanoate and 1.23 ml of triethylamine, followed by stirring at 110° C. for 3 days. After leaving to be cooled at room temperature, water and diisopropyl ether were added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.52 g of ethyl 8-(cyclohexylmethoxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:5]([O:27][CH2:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)[CH:4]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:5]([O:27][CH2:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)[CH:4]=1
Reactant: COc1ccc(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OCc2cc(C)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)CCNCC3)c(OCc2cc(C)ccn2)c1

Procedure:
1,1-dimethylethyl 7-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (4.8 g) was dissolved in dioxane (20 ml). Gaseous hydrogen chloride was passed through the reaction mixture for 1.5 h. The reaction was monitored by TLC. On completion the solid formed was collected by filtration and washed with acetone. The solid was then dissolved in water and the mixture was brought to pH8 using aqueous sodium bicarbonate. The sticky solid observed was extracted with DCM. The organics were dried over sodium sulphate and concentrated in vacuo to yield a solid. This was purified by column chromatography eluting with 0-8% methanol in DCM. Appropriate fractions were combined and concentrated in vacuo to yield a solid. This was triturated in diethyl ether to yield the title compound, 1.7 g (45%).
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([O-])=O.C(=O)([O-])O.[Na+]>CO>[NH2:5][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.3 %

Procedure:
Concentrated hydrochloric acid (1.00 ml, 12.0 mmol) and anhydrous tin dichloride (905 mg, 4.77 mmol) were sequentially added at 0° C. to a methanol (5 ml) solution of 4-[2-nitro-4-(trifluoromethyl)phenyl]morpholine (263 mg, 0.952 mmol), obtained as described in Referential Example 5-1. The resulting mixture was warmed to room temperature and stirred for 20 hours. A saturated solution of sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=2/1). Thus, 4-[2-amino-4-(trifluoromethyl)phenyl]morpholine (214 mg, 91.2%) was yielded as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]
Reactant: Clc1n[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)C=Cc1cccnc1
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CCXXIII was prepared from 5-bromo-3-chloro-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)C.C[Si](I)(C)C>C(Cl)(Cl)Cl>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:10]([CH:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Agent: C[Si](C)(C)I
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 8a (3 g, 7.7 mmol) in chloroform (50 mL) were added ethanol (2.25 mL, 38.6 mmol) and trimethylsilyl iodide (5.25 mL, 38.6 mmol). The mixture was stirred at 100° C. for 2 h in a sealed tube. The reaction was allowed to cool to rt and washed with 1 N NaOH, aqueous Na2S2O4, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated, to yield title compound 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthene-3-carboxylic acid diethylamide, 9a (3.0 g, 0.53 mmol). MS m/z=391.4 (MH+)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH2:31][CH2:32][C:33]1[O:34][CH:35]=[CH:36][CH:37]=1.CC(O)C>O>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[CH2:32][NH:31][C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: NCc1ccco1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1cc(NCc2ccco2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Yield: 29.6 %

Procedure:
(see, e.g., WO2013039988A1). A pressure vessel was charged with 50 (119 mg, 0.28 mmol), 2-aminomethylfuran (0.12 mL, 1.36 mmol) and iPrOH (4 mL). The vessel was sealed and the reaction mixture was heated at 100° C. overnight. An additional 1 mL (11.3 mmol) of amine was added and the mixture was heated at 150° C. overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL×2). Combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (40 mg, 30%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 7.07 (t, J=7.3 Hz, 1H), 6.97 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 6.80 (s, 1H), 6.30 (s, 1H), 6.22 (s, 1H), 5.47 (s, 2H), 5.14 (t, J=5.4 Hz, 1H), 4.68 (d, J=5.5 Hz, 2H), 4.43 (q, J=7.1 Hz, 2H), 2.58 (s, 3H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.83, 157.16, 156.86, 156.51, 152.16, 152.06, 141.97, 141.27, 134.71, 132.57, 129.67, 129.44, 123.17, 118.82, 110.40, 107.27, 106.91, 104.45, 61.66, 49.53, 38.75, 16.15, 14.23. ESI MS: m/z 483.1 (M+H)+.