Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([C@@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([N:21](C)[C:22](=O)OC(C)(C)C)[S:10]2)[C@H:6]1[O:30]CC=C)C=C.CCN(CC)CC.C(O)=O>O1CCOCC1.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>[CH3:22][NH:21][C:9]1[S:10][C@H:11]2[O:12][C@H:13]([C@@:14]([OH:20])([CH3:19])[C:15]([F:16])([F:17])[F:18])[C@@H:5]([OH:4])[C@H:6]([OH:30])[C@H:7]2[N:8]=1
Reactant: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H]([C@](C)(O)C(F)(F)F)[C@H]1OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: CNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of 119 (4.5 g, 9 mmol) in 1,4-dioxane (50 mL) was added Pd(PPh3)4 (2.1 g, 1.8 mmol), Et3N (23 g, 22.7 mmol) and HCOOH (0.8 g, 18 mmol) at 25° C. under N2 atmosphere. After 20 min at 60° C., additional HCOOH (6.3 g, 136 mmol) was added and the mixture was stirred for additional 12 hours at 60° C., then quenched by H2O (60 mL), extracted with dichloromethane (2×40 mL) to remove the organic impurities. The pH value of aqueous phase was adjusted to 7-8 by saturated aqueous NaHCO3, then concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 2%-10% methanol in dichloromethane to give the mixture of the two epimer. Further separation by Prep HPLC [(Agilent 1200 prep HPLC): Column, Sun Fire Prep C18*50 mm 5 um; mobile phase, WATER with CH3CN (5% CH3CN up to 40% in 10 min); Detector, UV, 220 nm] to afford (3aR,5S,6S,7R,7aR)-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as white solid (730 mg, 25.4%), Faster eluting isomer. (ES, m/z): 317.0; 1HNMR (300 MHz, D2O) δ 6.27 (d, J=6.9 Hz, 1H), 4.38-4.41 (m, 1H), 4.22-4.23 (m, 1H), 3.94-3.97 (d, J=8.4 Hz, 1H), 3.56-3.60 (d, J=8.4 Hz, 1H), 2.77 (s, 3H), 1.34 (s, 31-1); and (3aR,5S,6S,7R,7aR)-2-(methylamino)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as white solid (810 mg, 28.2%), Slower eluting isomer. (ES, m/z): 317.0; 1HNMR (300 MHz, D2O) δ 6.26 (d, J=6.9 Hz, 1H), 4.37-4.39 (m, 1H), 4.18-4.20 (m, 1H), 3.96-3.99 (m, 1H), 3.60-3.62 (d, J=8.4 Hz, 1H), 2.77 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:6]CS([O-])(=O)=O.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=[O:31])[C:24]=2[CH:23]=[CH:22]1>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:6][N:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=[O:31])[C:24]=2[CH:23]=[CH:22]1
Reactant: O=S(=O)([O-])CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 82.9 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.80 g of [3,5-bis(trifluoromethyl)benzyl]methanesulfonate and 2.00 g of indole-4-carbaldehyde as a starting material to give 4.24 g of 1-[3,5-bis(trifluoromethyl)benzyl]indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 83%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=1.O.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:22]#[N:23])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1ccc(C#N)c(C#N)c1
Temperature: 100 °C

Procedure:
4-Cyano-3-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester (from L-819,063 step 1, 4.92 g, 16 mmol) was dissolved in DMF (22.9 ml) and treated with Zn(CN)2 (1.3 g, 11.2 mmol). The reaction mixture was degassed by bubbling in argon for 1 hr. Pd(PPh3)4 (924 mg, 0.8 mmol) was then added and the reaction was heated to 100° C. for 15 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with water (2×10 mL), 5% HCl (1×10 mL), brine (1×10 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (100% CH2Cl2) to yield the desired compound. FAB MS: 187 m/z (M+ +H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[C:13][Si](C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]#[CH:13]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the intermediate from step A (2.7 g, 10 mmol) in 10:1 MeOH:H2O (60 mL) was added potassium carbonate (2.76 g, 20 mmol). The reaction was stirred at room temperature for 15 minutes after which the mixture was poured into a pH 7-phosphate buffer and extracted with methylene chloride (3×). The combined organic layers were then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was used without further purification. 1H NMR (CDCl3, 500 MHz): 7.8 (d, J=1.9 Hz, 1H), 7.5 (m, 2H), 3.48 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:20][CH2:19][O:18][C:17]([CH3:22])([CH3:21])[CH2:16]1>>[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:20][CH2:19][O:18][C:17]([CH3:21])([CH3:22])[CH2:16]1
Reactant: CN1C(=O)CCc2cc(I)ccc21
Reactant: CC1(C)CC(O)(c2csc(S)c2)CCO1
Product: CN1C(=O)CCc2cc(Sc3cc(C4(O)CCOC(C)(C)C4)cs3)ccc21
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-hydroxy-4-(2-mercaptothien-4-yl)-2,2-dimethyltetrahydropyran to give 4-hydroxy-2,2-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 72% yield as a foam;
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][S:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: C[S-]
Reactant: Cc1cccc(Nc2ncnc3ccc(CBr)cc23)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCc1ccc2ncnc(Nc3cccc(C)c3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
Sodium methanethiolate (0.141 g) was added to a stirred mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.6 g), triethylamine (0.203 g) and DMF (2 ml). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained an oil which was triturated under a mixture of hexane and diethyl ether to give 4-(3'-methylanilino)-6-methylthiomethylquinazoline (0.205 g), m.p. 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][C:38]([F:44])([F:37])[CH2:39][CH2:40]4)=[O:22])[C:15]=3[N:14]=2)=[O:35])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCC(F)(F)CC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(4,4-difluoro-piperidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 870 mg (1.70 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 302.3 mg (1.87 mmol) 4,4-difluoro-piperidine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: [CH3:1][CH2:2][CH3:3].[F:4][C:5]([F:12])([F:11])[C:6]([F:10])=[C:7]([F:9])[F:8]>>[F:4][C:5]([F:12])([F:11])[CH:6]([F:10])[C:7]([F:9])([F:8])[CH:2]([CH3:3])[CH3:1]
Reactant: CCC
Reactant: FC(F)=C(F)C(F)(F)F
Product: CC(C)C(F)(F)C(F)C(F)(F)F

Procedure:
n-Propane-(1.50 g., 34.2 mmole) and hexafluoropropene (1.71 g., 11.4 mmole) were heated together at 295° for 4 days in a 300 ml. Pyrex ampoule to give: (i) hexafluoropropene (0.55 g., 3.68 mmole; 32% recovery); (ii) n-propane (1.13 g., 25.5 mmole; 75% recovery); (iii) 1,1,1,2,3,3,-hexafluoro-4-methylpentane (CH3)2CH.CF2. CHF CF3 (1.20 g., 6.1 mmole; 80% based on C3F6 consumed) (Found: C, 37.4; H, 4.4; F, 58.1%; M, 194. C6H8F6 requires C, 37.2; H, 4.2; F, 58.6%; M, 194) b.p. 79.8° C. Reaction carried out at 330° C between n-propane and hexafluoropropene and on the same scale as above gave a lower yield (62% based on C3F6 consumed) of 1,1,1,2,3,3-hexafluoro-4-methylpentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[CH3:10][O:11][C:12](=[O:32])[C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:21]1[CH:22]=[C:13]([C:12]([O:11][CH3:10])=[O:32])[CH:14]=[CH:15][C:16]=1[C:17](=[O:18])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1ccc(C(=O)OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine and 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-terephthalic acid dimethyl ester to provide 277. LC-MS (M+H=289, obsd.=289).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O1CCCC1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>O>[Cl:12][C:13]1[N:18]=[C:17]([O:4][CH2:3][CH2:2][F:1])[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FCCOc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
2-Fluoroethanol (0.30 mL, 4.95 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution containing sodium hydride (60% NaH, 200 mg, 4.95 mmol), and an anhydrous tetrahydrofuran (5 mL) solution having 2,4-dichloropyrimidine (104, 500 mg, 3.30 mmol) dissolved therein was slowly added. The reaction mixture was stirred for 30 minutes and water was added. Organic compounds were extracted with ethyl acetate. Then, the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give 2-chloro-4-(2-fluoroethoxy)pyrimidine (106a, 237 mg, 41%) as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][N:16]1[CH2:21][C@H:20]([CH3:22])[NH:19][C@@H:18]([CH3:23])[C:17]1=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][C@H:18]1[C:17](=[O:24])[N:16]([CH3:15])[CH2:21][C@H:20]([CH3:22])[N:19]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: C[C@@H]1N[C@@H](C)CN(C)C1=O
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C)C(=O)[C@@H]3C)nc12
Yield: 19.1 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (342 mg, 1.62 mmol), (3S,5S)-1,3,5-trimethylpiperazin-2-one (230 mg, 1.62 mmol) and potassium carbonate (670 mg, 4.85 mmol), in DMF (10 mL), was stirred at ambient temperature for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with 0.5 N HCl (10 mL), H2O (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solids were removed by filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 10% CH2Cl2 in EtOAc to 100% EtOAc) to give methyl 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (98 mg, 19%): 1H NMR consistent.
Reaction SMILES: [CH2:1]([S:3][CH:4](O)[CH3:5])[CH3:2].C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18].[O:36]1CCCC1>>[CH2:1]([S:3][CH2:4][CH2:5][O:18][C:17](=[O:36])[C:16]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:15]=1[Cl:14])[CH3:2]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: C1CCOC1
Reactant: CCSC(C)O
Solvent: CCN(CC)CC
Product: CCSCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 53 %

Procedure:
In 20 ml tetrahydrofuran were dissolved 0.8 g (0.0075 mol) of ethyl thioethanol and 0.8 g (0.0079 mol) of triethylamine, and while heating to 60°-80° C., 1.6 g (0.0043 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride was added. After 5-hour stirring, the resulting mixture was cooled, freed of the solvent under reduced pressure, and extracted with benzene. The extract was washed with a dilute aqueous solution of caustic soda and then with dilute hydrochloric acid, and dehydrated with sodiumsulfate. By concentration, 1.0 g (0.0023 mol) of the intended product was obtained as an oily substance; yield 53.0%, nD23 1.5500.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 0 °C
Yield: 56.4 %

Procedure:
In 2.5 ml of pyridine were dissolved 0.25 g of 2'-deoxy-5-fluorouridine and 0.34 g of trityl chloride, and the solution was reacted at 60° C. for 4 hours under stirring. After completion of the reaction, the reaction mixture was poured into 80 ml of ice-cold water and precipitated crystals were collected by filtration. These crystals were dissolved in 30 ml of ethyl acetate, washed with saturated saline solution, dried over anhydrous magensium sulfate and condensed under reduced pressure. The residue obtained was applied to silica gel column chromatography to give 0.28 g (Yield: 56%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:44])[NH:15][C:16]2[N:25]3[CH2:26][CH2:27][N:28]=[C:24]3[C:23]3[CH:22]=[CH:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][S:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)(=[O:35])=[O:34])=[C:19]([O:42][CH3:43])[C:18]=3[N:17]=2)=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCN(CC)CC>[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([NH:15][C:16]2[N:25]3[CH2:26][CH2:27][N:28]=[C:24]3[C:23]3[CH:22]=[CH:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][S:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)(=[O:35])=[O:34])=[C:19]([O:42][CH3:43])[C:18]=3[N:17]=2)=[O:44])=[CH:10][N:9]=1
Reactant: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(NC(=O)OC(C)(C)C)nc1)N1CCN=C21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 48 h
Yield: 121.5 %

Procedure:
tert-Butyl[5-({7-methoxy-8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}carbamoyl)pyrimidin-2-yl]carbamate (Step 1, 150 mg 0.26 mmol) was dissolved in CH2Cl2 (15 mL) and TFA (0.16 mL, 2.1 mmol) was added dropwise. The mixture was stirred at rt over 2 d, after which 5 drops of Et3N were added causing a solid to precipitate. The mixture was stirred overnight, then the solvents removed under reduced pressure. The resulting residue was triturated in EtOAc (15 mL), collected by vacuum filtration and washed further with EtOAc (10 mL). This solid was then triturated in water (5 mL) collected by vacuum filtration and washed further with water (10 mL). High vacuum drying gave the title compound (172 mg, 92%): HPLC MS RT=0.87 min, MH+=545.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.21-2.26 (2H, m), 3.15-3.18 (4H, m), 3.24-3.29 (2H, m), 3.61-3.65 (4H, m), 3.99 (3H, s), 4.18-4.25 (2H, m), 4.37 (2H, t), 4.48-4.55 (2H, m), 7.44 (1H, d), 8.02 (1H, d), 9.06 (2H, s).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])#[N:2].[H][H].[ClH:19]>[Pt]=O.C(O)C.C(OCC)(=O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc2n(c1CC#N)CCCC2
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2n(c1CCN)CCCC2

Procedure:
Methyl 3-(Cyanomethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate 120b was hydrogenated with platinum oxide catalyst under 50 psi of hydrogen in ethanol and ethyl acetate in the presence of hydrogen chloride overnight at room temperature to give 120c (380 mg, 1.74 mmol) which was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=N/NC(N)=O)=[C:4]([N+:15]([O-])=O)[CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.[Rh]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:9][NH:15]2)=[CH:6][CH:7]=1
Reactant: NC(=O)N/N=C/Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
To a stirred suspension of (1E)-(4-fluoro-2-nitrophenyl)ethanal semicarbazone (27.0 g, 0.110 mol) in THF (750 mL) in a 1 L bomb was added Rh/C (5%; 3.5 g, 0.002 mol Rh) slurried in toluene and Fe(OAc)2 (2.9 g, 0.017 mol). The bomb was charged with H2 to 50 atm and stirred at room temperature for 2 days. The reaction mixture was filtered through celite, washing with MeOH (150 mL). The filtrate was concentrated to give a black oil that was partitioned between DCM (500 mL) and water (300 mL). The layers were separated and the aqueous fraction was extracted with DCM (2×200 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and treated with flash silica to decolourise the solution. The mixture was filtered concentrated under reduced pressure, giving 12.9 g (87%) of the title compound.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>C1(C)C=CC=CC=1.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>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:28]=[CH2:29])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2oc(-c3cc4ccccc4cn3)cc(=NOC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
In a sealed tube was degassed with argon for 15 min. a solution of 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (100 mg, 0.236 mmol) in toluene. Tributyl(vinyl)tin (76 μl, 0.26 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol) were added degassing was continued for 5 min. The tube was sealed and heated at 120° C. for 8 hours. The mixture was filtered, concentrated and purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-10%) to yield 2-isoquinolin-3-yl-6-(vinyl)-chromen-4-one O-tert-butyl oxime (84 mg, 96%).
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:25]=[CH:24][NH:23][C:17]=4[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>O1CCCC1>[CH:1]1([C@H:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[C:25]([I:26])=[CH:24][NH:23][C:17]=4[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(-c2cnn(C(CC#N)C3CCCC3)c2)c2cc[nH]c2n1
Solvent: C1CCOC1
Product: COc1nc(-c2cnn([C@H](CC#N)C3CCCC3)c2)c2c(I)c[nH]c2n1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a solution of 3-cyclopentyl-3-[4-(2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.532 g, 1.58 mmol) in tetrahydrofuran (20 mL) was added N-iodosuccinimide (0.36 g, 1.6 mmol). The reaction was stirred for 30 min and the solvent was removed in vacuo. The residue was purified by flash column chromatography, eluting with a gradient from 0-65% ethyl acetate in hexanes to afford a yellow solid (250 mg, 34%). 1H NMR (300 MHz, CDCl3): δ 10.31 (br s, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.29 (s, 1H), 4.34-4.21 (m, 1H), 4.06 (s, 3H), 3.14 (dd, 1H), 3.03-2.90 (m, 1H), 2.66-2.49 (m, 1H), 2.02-1.17 (m, 8H); LCMS (M+H)+: 463.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:11][CH2:12][N:13]([C:2]2[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:14]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: N#Cc1nccnc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nccnc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 12 the 2-chloro-3-cyanopyrazine (J. Chem. Soc., Perkin Trans. 1 1991, 11, 2877-81) was treated with 2,3,4,5-tetrahydro-1 H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyl-diisopropylamine in N,N-dimethylformamide at room temperature followed by 60° C. to yield the 3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as light yellow solid; MS: 251 (M+H)+.