Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The reaction mixture was composed of 100 mM TES buffer (pH 7.0), 5 mM L-proline, 5mM 2-ketoglutaric acid, 1 mM ferrous sulfate, 5 mM L-ascorbic acid and a predetermined amount of the pure enzyme, the total volume being 100 μl. The reaction was initiated by addition of the enzyme and continued for 10 minutes at 35° C. The reaction was stopped by heating the reaction mixture at 100° C. for 2 minutes. The amount of cis-3-hydroxy-L-proline formed in the reaction mixture was determined by the pre-column derivatization method using HPLC. One hundred microliters of 0.3M boric acid buffer (pH 10.7), 4 μl of an aqueous solution of 10% (v/v) mercaptoethanol and 16 μl of ethanol solution of 5% (w/v) OPA were added to 100 μl of the reaction mixture, and the mixture was allowed to stand at 60° C. for 30 seconds. In addition, 50 μl of ethanol solution of 2% (w/v) NBD was added thereto and the mixture was allowed to stand at 60° C. for 40 minutes. The reaction was stopped by adding 30 μl of 1N HCl to the reaction mixture, and the precipitates formed were removed therefrom by centrifugation and filtration. The cis-3-hydroxy-L-proline formed by the reaction was quantitatively determined by HPLC analysis.
Reaction SMILES: [CH2:1](O)[CH3:2].[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:1][CH3:2])=[O:10]
Reactant: O=C(O)CCCCCl
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCl
Yield: 71.5 %

Procedure:
Toluene (100 ml), ethanol (10.12 g, 219.65 mmol) and 5-chlorovaleric acid (25 g, 183.04 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (5.22 g, 27.46 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (4.63 g, 45.76 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl 5-chlorovalerate (21.54 g, 72%) was isolated in distillation.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][S:8][CH2:7]1)=O.[CH3:19][C:20]1[N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1>>[CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[C:6]2[CH2:7][S:8][CH2:9][CH2:10][C:11]=2[N:34]=[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:26][CH:27]=2)[N:33]=1
Reactant: COC(C(=O)C1CSCCC1=O)c1ccccc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: COC(c1ccccc1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CSCC2
Yield: 11 %

Procedure:
4-(Methoxy(phenyl)methyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (31.5 mg, 11%) was synthesised from 3-(2-methoxy-2-phenylacetyl)dihydro-2H-thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 444.0 (M+H)+
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:17])[C:14]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[O:15])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)n1ccc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1cc(C(=O)C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 52.4 %

Procedure:
The title compound was prepared according to general procedure C described in Scheme 2. N-Isopropylindole (1 g, 6 mmol) was treated with ether (10 mL), cooled to 0° C. and treated dropwise with oxalyl chloride (0.62 mL, 7 mmol). The reaction was gradually warmed to RT over a 3 h period affording a yellow precipitate. The reaction mixture was concentrated under reduced pressure and the resulting yellow solid was dissolved in DCM (20 mL) cooled to 0° C. and treated with a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.5 g, 7 mmol) and triethylamine (5.2 mL, 38 mmol) in DCM (10 mL). The reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified on silica gel (Biotage, 15-50% EtOAc/Hexanes, 30 min.) to provide the title compound as a yellow oil (1.3 g, 50% yield).
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=CN=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].O1C2=[CH:19][N:20]=CC=C2C=C1.O1C2C=CN=CC=2C=C1>>[S:1]([C:5]1[O:13][C:12]2=[CH:11][N:20]=[CH:19][CH:8]=[C:7]2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2cnccc2o1
Reactant: c1cc2ccoc2cn1
Agent: c1cc2occc2cn1
Product: NS(=O)(=O)c1cc2ccncc2o1
Yield: 40 %

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-sulfamoylfuro[3,2-c]pyridine except furo[2,3-c]pyridine was substituted for furo[3,2-c]pyridine. This compound was obtained in 40% yield after recrystallization from ethyl acetate, m.p. 199°-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(O)C.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.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:28]2[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=[C:26]([F:25])[CH:27]=2)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1c(Br)ccc(N)c1C#N
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(C(F)(F)F)c2)ccc(N)c1C#N
Temperature: 80 °C
Reaction time: 7 h
Yield: 103 %

Procedure:
Under a dry nitrogen atmosphere, 0.5 gram (0.0004 mole) of tetrakis(triphenylphosphine)palladium(0) was added to a stirred mixture of 2.8 grams (0.0132 mole) of 2-amino-5-bromo-6-methylbenzonitrile (prepared as in Step C of Example 1), 35 mL of aqueous 2M sodium carbonate and 50 mL of toluene. To this was then added dropwise a solution of 3.3 grams (0.0159 mole) of 3-fluoro-5-trifluoromethylphenylboronic acid in 10 mL of ethanol. Upon completion of addition, the reaction mixture was warmed to about 80° C., where it was stirred for seven hours. After this time the reaction mixture was poured into 200 mL of water. The mixture was then extracted with four 100 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 2-amino-6-methyl-5-(3-fluoro-5-trifluoromethylphenyl)benzonitrile, mp 96°-97° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH-:4].[C:5]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:24][C:23]3[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=3[N:17]=2)=[CH:12][CH:11]=1)([OH:7])=[O:6].O[N:34]1[C:55](=[O:56])[NH:54][C@H:53]2[C@@H:35]1[CH2:36][S:37][C@H:38]2[CH2:39][CH2:40][CH2:41][CH:42](N1C(=O)CCC1=O)[C:43](=[O:45])O.CO.CCOCC>CN(C=O)C>[C:43]([NH:1][CH2:2][CH2:3][NH-:4])(=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[C@@H:53]2[C@@H:35]([NH:34][C:55]([NH:54]2)=[O:56])[CH2:36][S:37]1.[C:5]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:24][C:23]3[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=3[N:17]=2)=[CH:14][CH:15]=1)([OH:7])=[O:6]
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Reactant: [NH-]CCN
Agent: CCCn1c(=O)c2[nH]c(-c3ccc(OCC(=O)O)cc3)nc2n(CCC)c1=O
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: [NH-]CCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Compound 6d (24.1 mg, 0.056 mmol) was suspended in 1 ml DMF. N-Hydroxysuccinimido-d-biotin (Sigma, 23.6 mg, 0.069 mmol) was added with stirring. A solution formed after several minutes, and a precipitate appeared soon thereafter. After one day methanol (1 ml) and ether were added. The precipitate was collected and dried (yield 26.6 mg, 73%).
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:30](Cl)(=O)[CH:31]([CH3:33])[CH3:32].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH:31]([C:33]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][CH:8]([CH:11]3[O:29][C:14]4=[CH:15][N:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=5)[CH:18]=[C:13]4[CH2:12]3)[CH2:9][CH2:10]2)[N:4]=1)([CH3:32])[CH3:30]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-hydroxy-4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (45 mg), isobutyryl chloride (12 μL), and triethylamine (50 μL) in tetrahydrofuran (5 mL) is stirred for 30 min at room temperature prior to heating to 80° C. for 5 h. The heating is continued over night at reflux. The reaction mixture is diluted with ethyl acetate after cooling to room temperature, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is triturated with a small amount of methanol and the precipitate is filtered off, washed with diethyl ether, and dried to give the title compound. LC (method 5): tR=1.30 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[H-].[Na+].[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[ClH:17].[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1)(=[O:4])=[O:3]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(S(N)(=O)=O)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
A solution of 5-aminosulphonyloxindole (355 mg, 1.67 mmol) in DMF (3.5 ml) was added dropwise to sodium hydride (67 mg, 1.67 mmol, prewashed with THF) in DMF (5 ml). The mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (150 mg, 0.56 mmol), (prepared as described for the starting material in Example 2), in DMF (3 ml) was added. The mixture was heated at 65° C. for 2.5 hours and then stirred overnight at ambient temperature. The mixture was partitioned between ethyl acetate and water, the aqueous layer was adjusted to pH7 with 1M hydrochloric acid and left standing for 2 hours. The resulting precipitate was collected by filtration, washed with water and ether, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 2.2M ethereal hydrogen chloride (1ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(5-aminosulphonyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (144 mg, 60%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@:7]([CH3:43])([CH2:41][OH:42])[C:8](=[O:40])[C@@H:9]([NH:17][C:18](=[O:39])[C@@H:19]([NH:23][C:24](=[O:38])[C@@H:25]([NH:29][C:30]([C:32]1[S:36][C:35]([CH3:37])=[N:34][CH:33]=1)=[O:31])[CH2:26][O:27][CH3:28])[CH2:20][O:21][CH3:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][S:2]([O:42][CH2:41][C@:7]([OH:6])([CH3:43])[C:8](=[O:40])[C@@H:9]([NH:17][C:18](=[O:39])[C@@H:19]([NH:23][C:24](=[O:38])[C@@H:25]([NH:29][C:30]([C:32]1[S:36][C:35]([CH3:37])=[N:34][CH:33]=1)=[O:31])[CH2:26][O:27][CH3:28])[CH2:20][O:21][CH3:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: CS(=O)(=O)Cl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(C)(=O)=O

Procedure:
Prepared according to procedures described above, by reacting methanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C26H36N4O10S2 m/z: 629 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].F[B-](F)(F)F.[C:10]([C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=1[N+]#N)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cu](SC#N)SC#N.O>[C:10]([C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=1[S:1][C:2]#[N:3])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reactant: N#C[S-]
Agent: N#CS[Cu]SC#N
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: O
Product: N#CSc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reaction time: 20 h

Procedure:
To a mixture of potassium thiocyanate (42 g), copper thiocyanate (4s g) and water (400 ml), 2-benzoyl-5-carboxy3-nitrobenzenediazonium tetrafluoroborate (prepared as described in Example 17, step A; 28 g) is added in portions while stirring at 45°-50° C. After the addition is completed, the mixture is stirred at about 50° C. for a further 4 hours and thereafter at room temperature for about 20 hours. The resulting precipitate is collected by filtration, washed with water and dried. The dried solids are then extracted with boiling ethanol (three portions of 250 ml, 100 ml, and 100 ml, respectively) and filtered hot. The combined filtrates are evaporated in vacuo and the residue is crystallized by trituration with 50% aqueous ethanol (100 ml). The material is collected by filtration, washed with cold 50% ethanol and dried. After recrystallization from aqueous ethanol, 4-benzoyl-5-nitro-3-thiocyanobenzoic acid is obtained with a melting point of 183.5°-184.5° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:44][CH:45]([F:47])[F:46])(=O)=O>>[F:46][CH:45]([F:47])[CH2:44][N:21]1[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:26]=[CH:27][N:28]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 44.9 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30.0 mg, 0.0694 mmol) in acetonitrile (694 μL, 0.0694 mmol) was added K2CO3 (38.4 mg, 0.278 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (29.7 mg, 0.139 mmol). After heating to 45° C. for 2 hours, the reaction was incomplete and another portion of 2,2-difluoroethyl trifluoromethanesulfonate (20.0 mg, 0.0936 mmol) was added to drive to completion. Purification of the crude reaction mixture by reverse phase HPLC afforded 2-(1-(2,2-difluoroethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (13.2 mg, 45% yield). MS (apci) m/z=424.2 (M+1-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:15][CH2:16][CH2:17][NH:18][NH2:19]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:18]([CH2:17][CH2:16][OH:15])[NH2:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNCCO
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: NN(CCO)c1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 5.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine and 5.02 g. of 2-hydroxyethylhydrazine in 75 ml. of butanol is heated at reflux overnight and then cooled in an ice bath. The precipitate is collected by filtration, washed with butanol, water and then dried. Recrystallization from ethanol gives crystals, m.p. 172°-174° C.
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH2:8]([O:15][CH2:16][CH:17]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][CH2:16][CH:17]1[O:6][CH2:5][C:2]([F:7])([F:1])[CH2:3][O:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CCOCc1ccccc1
Reactant: OCC(F)(F)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC1(F)COC(COCc2ccccc2)OC1
Yield: 42.8 %

Procedure:
A mixture of 2,2-difluoropropane-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1.34 g, 8.9 mmol), p-toluenesulfonic acid monohydrate (154 mg, 0.81 mmol) and toluene (20 ml) was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour. The resultant mixture was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and silica gel was added thereto. The resultant mixture was concentrated to dryness and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1) to obtain the title compound (930 mg, 42.8%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[O:16][CH:17]=[CH:18][C:19]=1[CH3:20].Cl>C(=S)=S>[CH3:20][C:19]1[CH:18]=[C:17]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[O:16][C:15]=1[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccoc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
Carbon disulfide (35 ml) was added to benzoyl chloride (7.3 g) and anhydrous aluminum chloride (7.0 g) under an argon atmosphere, and a solution of 2,3-dimethylfuran (5.0 g) in carbon disulfide (35 ml) was added dropwise thereto at 10° C. The mixture was then stirred for 30 min while raising the temperature to room temperature. 10% Hydrochloric acid (200 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane layer was then washed with water and a 5% aqueous sodium bicarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-phenyl-methanone (2.5 g, yield 25%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[Sn](Cl)Cl>Cl>[NH:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12])[NH2:1]
Reactant: O=N[O-]
Reactant: Cc1ccncc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1ccncc1NN

Procedure:
2.55 ml of a 2.5 M aqueous sodium nitrite solution are added to a solution of 4.0 g (37 mmol) of 3-amino-4-methylpyridine in 19 ml of 6 N hydrochloric acid while cooling in an ice/salt bath. The resulting diazonium salt solution is slowly added dropwise at −10° C. to −15° C. to a solution of 21 g (111 mmol) of tin(II) chloride in 26 ml of hydrochloric acid. The solution is left to stand in a refrigerator overnight in order to complete the reaction. The precipitated solid is filtered off with suction, suspended in 26 ml of water, made basic with concentrated sodium hydroxide solution and filtered. The filtrate is extracted ten times with 20 ml of dichloromethane each time, and the combined organic phases are dried over sodium sulphate and concentrated. Drying under high vacuum results in 1.45 g (31% of theory) of the desired product as a colourless oil.
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[C:17]([CH3:24])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:25]([C:27]1[C:32]2[N:33]([CH2:36][C:37](O)=[O:38])[CH:34]=[N:35][C:31]=2[CH:30]=[CH:29][CH:28]=1)#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH:23][C:37](=[O:38])[CH2:36][N:33]2[C:32]3[C:27]([C:25]#[N:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:35]=[CH:34]2)[CH3:22])=[C:17]([CH3:24])[CH:16]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: Cc1cc(C(C)(C)C)ncc1C(C)N
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C(C)(C)C)ncc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-4-methylpyridin-3-yl)ethyl]amine (intermediate 28) (52 mg, 0.27 mmol), 7-cyanobenzimidazole-1-acetic acid (54.4 mg, 0.27 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (117 μL, 2.5 mmol). Water is added and the reaction is concentrated then purified by reverse phase chromatography. (Yield 31.3 mg, 31%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.27 (s, 9 H), 1.42 (d, J=7.03 Hz, 3 H), 2.29 (s, 3 H), 5.03-5.12 (m, 1 H), 5.13-5.27 (m, 2 H), 7.17 (s, 1 H), 7.34 (dd, J=8.11, 7.71 Hz, 1 H), 7.71 (dd, J=7.62, 0.78 Hz, 1 H), 8.01 (dd, J=8.01, 0.98 Hz, 1 H), 8.34 (s, 1 H), 8.47 (s, 1 H), 8.88 (d, J=7.81 Hz, 1 H). MS [MH+] calc. 376.2137 found 376.3.