Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10](CC=O)[CH2:9]1)=O)(C)(C)C.N1([C:20]2[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=2)C=NC=N1.[C:28]([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[N:8]1([C:6]2[NH:26][C:23]3[C:24]([CH:28]=2)=[CH:25][CH:20]=[CH:21][CH:22]=3)[CH2:9][CH2:10][CH2:11]1
Reactant: NNc1ccc(-n2cncn2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CC=O)C1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]c(N3CCC3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
N-tert-Butyloxycarbonyl-3-formylmethylazetidine (0.4 g, 2.01 mmol) was added to a solution of 4-(1,2,4-triazol-1-yl)phenylhydrazine (0.35 g, 2.01 mmol) in 4% H2SO4 (50 ml) and the mixture refiuxed for 16h. The mixture was then cooled to room temperature, basified (K2CO3) and extracted with n-butanol (5 x). The crude product obtained was chromatographed on silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1) to give the title-azetidinylindole (0.186 g, 39%); δ (360 MHz, CD3OD) 3.80-3.88 (4H, m, 2 of CH2 of azetidine), 4.12-4.23 (1H, m, CH), 7.23 (1H, s, Ar--H), 7.39 (2H, s, Ar--H), 7.65 (1H, d, J=2.5 Hz, Ar--H), 8.04 (1H, s, Ar--H), 8.89 (1H, s, Ar--H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1)(=[O:33])=[O:32]>>[ClH:1].[CH3:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[C:38]([NH:42][C:2]2[N:7]=[C:6]([N:8]([CH3:29])[C:9]3[CH:28]=[CH:27][C:12]4[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][CH:41]=1)(=[O:32])=[O:33]
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)CCc1cccc(N)c1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5cccc(CCS(C)(=O)=O)c5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 3-(2-Methanesulfonyl-ethyl)-phenylamine (40 mg, 0.20 mmol) as a white solid (69 mg, 57%). 1H NMR (300 MHz, ds-DMSO) δ 9.08 (s, 1H), 7.76 (d, J=6.0 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.28-7.34 (m, 3H), 7.08-7.23 (m, 3H), 6.79-6.89 (m, 4H), 5.61 (d, J=5.7 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.43 (s, 3H), 3.35-3.40 (M, 2H), 2.97 (s, 3H), 2.90-2.94 (m, 2H). MS (ESI) m/z=572 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:19](=[O:22])(=[O:21])[NH2:20])[C:17]=1[Cl:18])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:25])C.OO.[OH2:29]>>[CH2:1]([S:8]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:19](=[O:22])(=[O:21])[NH2:20])[C:17]=1[Cl:18])[C:12]([OH:14])=[O:13])(=[O:25])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cl
Reactant: CC(=O)O
Agent: OO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(S(=O)(=O)Cc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-benzylthio-4-chloro-5-sulfamylbenzoic acid (0.75 g), acetic acid (25 ml), and hydrogen peroxide (2 ml of an 30% aqueous solution) is stirred for 2 days at room temperature. Addition of water (100 ml) precipitates 3-benzylsulconyl-4-chloro-5-sulfamylbenzoic acid. After collection by filtration and recrystallization from aqueous ethanol the compound crystallizing with one mole of water, is obtained with a melting point of 236° - 237°C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[NH:14][CH:13]=[CH:12][N:10]3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:14]1[C:9]2[N:10]([N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[CH:12]=[CH:13]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2cc3[nH]ccn3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccn2nc(-c3ccccc3)cc12
Reaction time: 1 h

Procedure:
A solution of 0.4 g of 6-phenyl-1H-imidazo[1,2-b]-pyrazole in 10 ml of dimethylformamide was slowly added dropwise, whilst stirring at room temperature, to 96 mg of a 55% w/w suspension of sodium hydride in mineral oil, which was itself suspended in 10 ml of dimethylformamide, and then the mixture was stirred for a further 1 hour. At the end of this time, 0.24 ml of ethyl bromoacetate and 10 ml of dimethylformamide were added, and then the whole mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate and water, and then the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified first by column chromatography through silica gel, eluted with a 1:1 by volume mixture of ethyl acetate and hexane, and then by recrystallization from a mixture of ethyl acetate and hexane, to give 0.38 g of the title compound in the form of plates melting at 85°-87° C.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=1[CH3:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=O)[CH2:25]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: COC(=O)c1cc(C(N)=S)c(C)s1
Product: COC(=O)c1cc(-c2nc(-c3ccc(OC)c(OC)c3)cs2)c(C)s1
Yield: 53 %

Procedure:
Methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-metltylthiophene-2-carboxylate: A solution of 257 mg (0.48 mmol, based on a mixture containing 60% nitrile) of methyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 124 mg (0.48 nmuol) of 2-bromo-(3′, 4′-dimethoxy)-acetophenone (Example 31, step (a)) was reacted in a manner similar to Example 8, step (a) to give methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate (95 mg, 53%) as a solid. Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H17NO4S2 376.1 (M+H), found 376.3.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH3:34][NH2:35]>C(Cl)(Cl)(Cl)Cl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:35][CH3:34])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CN
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)NC)c(=O)oc12
Reaction time: 0.67 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in CCl4 (15 mL), added thionyl chloride (1.0 mL), was refluxed for 2.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in CCl4 (10 mL). The solvent was eliminated under reduced pressure. Dispersion in CCl4 and solvent elimination was repeated twice. The residue was dissolved in CCl4(10 mL) and added with stirring to a solution of the methyl amine (0.04 g, 1.28 mmol). After 40 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N-methyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.33 g, 65% yield). White solid, m. p. 215-216° C.; 1H NMR (CDCl3 300 MHz): δ 8.93 (s, 1H), 8.72, (brd, J=4.6 Hz, 1H) 7.96 (d, J=8.1 Hz, 2H), 7.83-7.77 (m, 3H), 7.55 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.49-3.37 (m, 1H), 3.04 (d, J=4.9 Hz, 3H), 2.45 (s, 3H), 1.80-1.71 (m, 2H), 1.35 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.5, 1610, 161.2, 153.1, 148.5, 144.1, 142.2, 136.5, 135.4, 132.2, 131.4, 129.5, 128.8, 127.1, 123.2, 119.0, 118.8, 33.6, 29.8, 26.7, 21.8, 20.6, 12.1; ESI-MS (m/z): 404 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:34].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:20]([OH:22])=[O:34])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1OC

Procedure:
In analogy with Example 44d), 778 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4-dimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 27.67 ml of dimethoxyethane and 13.91 ml of water are hydrolysed with 6.83 ml of 1M lithium hydroxide solution to give the title compound, which is subjected directly to further processing. TLC Rf (C)=0.07.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:32][OH:33])[C@@H:9]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:10]([NH:20][C:21](=[O:23])[CH3:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH:40]=[CH2:41].[I:44]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:32][O:33][CH:40]([O:39][CH2:38][CH2:37][C:36]([CH3:43])([CH3:42])[CH3:35])[CH2:41][I:44])[C@@H:9]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:10]([NH:20][C:21](=[O:23])[CH3:22])[CH2:11][C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C=COCCC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@@H](COC(CI)OCCC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 69.7 %

Procedure:
Dissolve [(1R,2S,3S)-3-acetylamino-2-benzyloxy-4-(3,5-difluorophenyl)-1-hydroxymethyl-butyl]-carbamic acid tert-butyl ester (0.52 g, 1.09 mmol) and 3,3-dimethyl-1-vinyloxybutane (0.15 g, 1.20 mmol) in acetonitrile (6 mL) and add N-iodosuccinimide (0.27 g, 1.20 mmol) at room temperature. Heat in oil bath at 80° C. for 2 hours 45 minutes. Cool to room temperature, dilute with ethyl acetate, wash with water or 10% aqueous sodium thiosulfate, saturated aqueous sodium chloride, concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 ethyl acetate:hexanes) to give the title compound (0.557 g, 70% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=3[F:24])[C:9]2=[O:25])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:27][C:28]1[N:29]=[CH:30][C:31]([N:4]2[CH2:5][CH2:6][CH:7]([N:8]3[CH2:12][CH2:11][C@H:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=4[F:24])[C:9]3=[O:25])[C:2]([CH3:26])([CH3:1])[CH2:3]2)=[N:32][CH:33]=1
Reactant: CC1(C)CNCCC1N1CC[C@H](Nc2ccc(S(C)(=O)=O)cc2F)C1=O
Reactant: Clc1cnc(Cl)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CN(c2cnc(Cl)cn2)CCC1N1CC[C@H](Nc2ccc(S(C)(=O)=O)cc2F)C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
To a solution of (3S)-1-(3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.010 g, 0.026 mmol) in DMF (1 mL) was added 2,5-dichloropyrazine (0.0078 g, 0.052 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.018 mL, 0.10 mmol) and the reaction was stirred for 3 hours at 100° C. The reaction was cooled, poured into brine and extracted into EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum. Reverse phase HPLC purification of the crude material gave (3S)-1-(1-(5-chloropyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.0023 g, 0.0046 mmol, 18% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.02 (s, 3H), 1.03 (s, 3H), 1.81-1.91 (m 1H), 2.12-2.21 (m, 1H), 2.71-2.81 (m, 2H), 2.95-3.05 (m, 2H), 3.03 (m, 3H), 3.52 (dd, 2H), 3.97 (d, 1H), 4.15-4.23 (m, 2H), 4.47-4.51 (m, 1H), 5.12 (bs, 1H), 6.80 (t, 1H), 7.55 (d, 1H), 7.61 (d, 1H), 7.90 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][C@H:13]1[C@H:17]([OH:18])[CH2:16][CH:15]=[CH:14]1.O1CCCC1.C[O:25][C:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])=O>C(N(CC)CC)C>[OH:18][C@@H:17]1[CH2:16][CH:15]=[CH:14][C@H:13]1[N:12]1[C:26](=[O:25])[C:28]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]2[C:30]1=[O:31]
Reactant: N[C@@H]1C=CC[C@H]1O
Reactant: COC(=O)c1ccccc1C(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A 31.3 g. (0.115M) quantity of dl-trans-3-amino-4-hydroxycyclopentene toluenesulfonate is dissolved in 240 ml. of tetrahydrofuran and 47 ml. (0.46M) of triethylamine. The resultant stirred solution is cooled to 5° and treated dropwise with 22.8 g. (0.115M) of o-methoxycarbonylbenzoylchloride. The reaction is then allowed to warm to 25°. After 48 hours the reaction is partitioned between Ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and concentrated in vacuo leaving 29.6 g. of residue. This residue is chromatographed over silica gel 60 eluted with 5 l. of (10-90) and 7.5 l. of (20-80) acetone-methylene chloride. Three hundred ml. fractions are collected. The product is isolated in fractions 25-34, which upon standing crystallizes to yield 14.2 g. of dl-trans-4-hydroxy-3-phthalido-cyclopentene, m.p. 114°-116°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C(OC)=O)[CH:3]=1.OO.NC(N)=[O:16].FC(F)(F)[C:20]([O:22][C:23](=[O:28])[C:24](F)(F)F)=O.Cl>ClCCl>[CH3:4][C:3]1[C:24]([C:23]([O:22][CH3:20])=[O:28])=[N+:5]([O-:16])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(F)ccn1
Reactant: NC(N)=O
Agent: Cl
Agent: OO
Solvent: ClCCl
Product: COC(=O)c1c(C)c(F)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-fluoropicolinate (2, 1 g, 6.45 mmol) in dichloromethane (30 mL) is added urea hydrogen peroxide (1.27 g, 13.54 mmol) and trifluoroacetic anhydride (1.79 mL, 12.9 mmol). The reaction is stirred at room temperature for 2 h. The resulting mixture is pour into 0.5 M hydrochloric acid and extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude is purified via flash chromatography to afford methyl 4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[O:13]1.Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:20]3[O:21][CH2:22][CH2:12][O:13][C:14]=3[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3,4-ethylenedioxyaniline (34 g, 225 mmol), MeOH (100 mL), H2O (300 mL) and 2,4-dichloro-5-fluoropyrimidine (25 g, 150 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with H2O (1.5 liter), acidified with 2N HCl (200 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to obtain 33 g (78%) of the desired product, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidincamine (R926087). 1H NMR (CDCl3): δ 8.02 (1H, d, J=3 Hz), 7.25 (d, 1H, J=1.2 Hz), 6.98 (dd, 1H, J=2.4 and 8.1 Hz), 6.85 (d, 1H, J=5.7 Hz), 4.27 (m, 4H); 19F NMR (CDCl3): −44570; LCMS: ret. time: 26.70 min.; purity 100%; MS (m/e): 283 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:13][C:12]2=O)=O)=[CH:4][CH:3]=1.[CH3:22][C:23]1[N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)[CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CCO>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:11]3[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:13][C:12]=3[N:36]=[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH3:22])=[CH:29][CH:30]=3)[N:37]=2)=[CH:4][CH:3]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCC(C(F)(F)F)CC1C(=O)Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CC(C(F)(F)F)CC3)cc1
Temperature: 130 °C
Yield: 24.9 %

Procedure:
2-(2-(4-Fluorophenyl)acetyl)-4-(trifluoromethyl)cyclohexanone (75 mg, 0.25 mmol), 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (53.4 mg, 0.25 mmol) and potassium carbonate (68.6 mg, 0.50 mmol) were added to a microwave vial. EtOH (3 mL) was added and the reaction was heated to 130° C. for 2 h. DCM (3 mL) and water (3 mL) were added. The organic phase was separated and the solvent was evaporated. The product was purified by preparative HPLC yielding 4-(4-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroquinazolin-2-amine (30.0 mg, 25.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].Cl[CH2:16][CH2:17][N:18]=[C:19]=[O:20].[S-2:21].[Na+].[Na+]>C(O)C>[Si:5]([CH2:4][CH2:3][CH2:2][NH:1][C:19]([NH:18][CH2:17][CH2:16][S:21][CH2:16][CH2:17][NH:18][C:19]([NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:20])=[O:20])([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C=NCCCl
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCSCCNC(=O)NCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: -78 °C
Yield: 96.7 %

Procedure:
In a first reaction step, 3-aminopropyltriethoxysilane (159.39 g, 0.72 mol, 1.00 eq) is initially charged in ethanol (3.0 l) in a 4 l three-neck flask with precision glass stirrer, internal thermometer, dropping funnel and reflux condenser, and cooled to −78° C. 2-Chloroethyl isocyanate (75.92 g, 0.72 mol, 1.00 eq) is added dropwise at −78 to −69° C. within 2.25 h and then the mixture is heated to 50° C. Dry sodium sulphide (Na2S, 28.09 g, 0.36 mol, 0.50 eq) is added in five portions and the mixture is heated to reflux. After a reaction time of 4.5 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—S—CH2CH2—NH—CO—NH—CH2CH2CH2—Si(OEt)3 product (214.09 g, 96.7% of theory) is obtained as a waxy, white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.I[CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:1]=[C:2]1[O:3][C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:7]1[CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:39])([CH3:40])[O:33]1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of (2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate (4.69 g, 13.27 mmol) and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (d 1.38, 5.96 mL, 8.23 g, 26.5 mmol, 2 equiv) in THF (66 mL, 0.2 M) and HMPA (6.6 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (14.6 mL, 1.0 M, 1.1 equiv) drop wise over 5 min and stirred for 1 h. After warming to room temperature and stirring for an additional 2 h, the solution was cooled to 0° C. and quenched with 0.5 N HC (2-3 equiv). The resulting solution was diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as a white solid (6.66 g, 94%); ESI-LCMS m/z calcd for C31H42BNO2: expected 535.3. found 536.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C@@H:11]3[C@@H:16]([C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14][CH2:13][NH:12]3.[CH2:17]([Cl:20])[CH:18]=[CH2:19].C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[ClH:20].[ClH:20].[CH2:19]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:16]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[O:9][CH2:10][C@@H:11]12)[CH:18]=[CH2:17]
Reactant: C=CCCl
Reactant: COc1cccc2c1OC[C@H]1NCCC[C@H]21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: C=CCN1CCC[C@@H]2c3cccc(OC)c3OC[C@H]21
Product: Cl

Procedure:
A mixture of 2.19 g of trans-7-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine, 0.80 g of allyl chloride, 2.0 g of calcium carbonate in 20 ml of dry dimethylformamide is heated at 80° for 16 hours. After dilution with water the product is extracted with ether. After drying over magnesium sulfate the solvent is removed in vacuo. Acidification with ethanolic hydrochloric acid affords trans-4-allyl-7-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride. Hydrogenation of said compound in the presence of 500 mg of 10% palladium on carbon catalyst at 3 atm. pressure for 6 hours at room temperature in water affords trans-7-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride.