Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[C:11](=[O:14])([O-])[O-].[K+].[K+].ClC[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:21]([C:30]([F:33])([F:32])[F:31])[CH:20]=1>CC(N(C)C)=O>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH2:11][O:14][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:20][C:21]=2[C:30]([F:31])([F:32])[F:33])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Temperature: 77 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
In a 1 L flask equipped with a stirrer, thermocouple, condenser and a nitrogen inlet, was placed nitrophenol (28 g, 201 mmol) in DMA (150 mL) and potassium carbonate powder (28.7 g, 207 mmol). 4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (45.4 g, 173 mmol) was added and washed in with DMA (120 mL). The reaction was heated at 80° C. (bath, internal 77° C.) overnight. The mixture was cooled and poured into ice water (1 L). The solids formed were allowed to settle with stirring for 4 h and collected by filtration. The solid collected was stirred in sodium bicarbonate solution (300 mL), filtered, washed with water, and air dried. The pale yellow residue was washed with hexanes (250 mL) and the solids were dried in vacuum oven overnight to give the title compound (41.4 g, 85% pure by LC). LCMS m/z=366.2 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]([CH3:14])([CH3:13])[C:10]([O-:12])=[O:11].[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:34][CH2:33]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:15]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:33][CH3:34])=[O:11])=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C1COCCO1
Reactant: CC(C)(Sc1ccccc1Br)C(=O)[O-]
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+]
Product: CCOC(=O)C(C)(C)Sc1ccccc1-c1ccc(C#N)cc1
Temperature: 80 °C
Yield: 57 %

Procedure:
A mixture of 2-(2-bromophenylthio)-2-methylpropanoate (151 mg, 0.5 mmol), 4-cyanophenyl boronic acid (76 mg, 0.5 mmol), aqueous sodium carbonate solution (2 M, 1 mL), and Pd(PPh3)4 (29 mg, 0.025 mmol) in dioxane (2 mL) was degassed for 15 minutes. The mixture was sealed and heated to 80° C. for 12 hours. The reaction mixture was washed with water, extracted with ethyl acetate, dried (MgSO4), concentrated and purified by chromatography to yield ethyl 2-(4′-cyanobiphenyl-2-ylthio)-2-methylpropanoate (93 mg, 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]#[N:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](Cl)(C)C.[N-:33]=[N+:34]=[N-:35].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]2[NH:35][N:34]=[N:33][N:20]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Agent: C[Sn](C)(C)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(c1cccc(OCc2ccccc2)c1)C(CCc1nnn[nH]1)c1ccccc1
Temperature: 115 °C
Reaction time: 30 h

Procedure:
A mixture of 1-(3-benzyloxyphenyl)-4-cyano-2-phenylbutan-1-one (2.2 g), toluene (80 mL), trimethyltin chloride (6.17 g) and sodium azide is stirred at 115° C. for 30 hours. The cooled reaction mixture is filtered and the insoluble material is washed with a little ethyl acetate. The combined filtrate plus washings are evaporated and the resulting orange oily solid (3 g) is subjected to flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (29:1 v/v), followed by crystallisation from a mixture of ethyl acetate and cyclohexane, to give 5-[4-(3-benzyloxyphenyl)-4-oxo-3-phenylbutyl]-1H-tetrazole (0.86 g), in the form of a white solid, m.p. 136-138° C. [Elemental analysis:- C,72.5;H,5.63; N,14.0%; Calculated:- C,72.3;H,5.56; N,14.1%].
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH2:20]([OH:23])[C:21]#[CH:22].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11]([C:22]#[C:21][CH2:20][OH:23])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCO)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate (1.38 g, 3.95 mmol) obtained in Example 47(c) was dissolved in dimethylformamide (20 ml), and then propargylalcohol (0.69 ml, 11.9 mmol), triethylamine (5.60 ml, 40.1 mmol), copper(I) iodide (76 mg, 0.40 mmol), and dichlorobis(triphenylphosphine)palladium (276 mg, 0.39 mmol) were added thereto followed by stirring for 1 hour at 80° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and after the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:3) to afford the title compound (685 mg, 54% yield) as a white crystalline solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.[CH2:28]([N:30](CC)CC)C.[CH:35]1([C:38]2[N:43]=[C:42]([C:44](=N)OCC)[CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36]1>C(O)C>[CH:35]1([C:38]2[N:43]=[C:42]([C:44]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][CH:13]([C:17]6[N:19]7[CH2:23][CH2:22][CH2:21][C:20]7=[CH:28][N:30]=6)[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH:41]=[CH:40][N:39]=2)[CH2:36][CH2:37]1
Reactant: Nc1ccc(N2CCCC(C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)c1ccnc(C2CC2)n1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: c1cc(-c2nc3ccc(N4CCCC(c5ncc6n5CCC6)C4)nc3[nH]2)nc(C2CC2)n1
Temperature: 70 °C

Procedure:
To a solution of (1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (18 mg, 0.06 mmol) and acetic acid (55 μL, 0.96 mmol) in ethanol (0.5 mL) was added triethylamine (17 μL, 0.12 mmol) followed by ethyl 2-cyclopropylpyrimidine-4-carbimidate (11.5 mg, 0.06 mmol) dissolved in ethanol (0.5 mL). The reaction mixture was heated to 70° C. for 1.25 h. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate and the undissolved solids were filtered off. The filtrate was washed with a saturated aqueous solution of ammonium chloride, washed with a saturated aqueous solution of sodium bicarbonate, and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 427.1; HPLC retention time 2.0183 (Method A).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].B1(C=C)OB([CH:33]=[CH2:34])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:33]=[CH2:34])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: [K+]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=Cc1nc(C(=O)OCCCC)c(O)c2ccc(Oc3ccccc3)cc12
Reaction time: 3 h

Procedure:
A mixture of 1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (416 mg, 1 mmol, see example D-28a), Pd(PPh3)4 (118 mg, 0.1 mmol), 2,4,6-Trivinylcyclotriboroxane-pyridine complex (241 mg, 1 mmol), K2CO3 (414 mg, 3 mmol), and 1,4-dioxane (8 ml) was refluxed with stirring under N2 protection for 3 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (5 ml) and the mixture was extracted with EtOAc (20 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes EtOAc=98 2 as the eluent gave the title compound as a yellowish solid (65 mg); MS-(+)-ion M+1=364.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[C:10]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:38]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:38][C:17]1[C:18]2[C:23]3=[C:22]4[C:21](=[CH:20][CH:19]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:9][C:10]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:11]4[CH:12]=[CH:13][C:14]3=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:16]=1
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(Br)c3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Next, a mixed solution of 1.5 g of 1,3,6-tri(4-methylphenyl)pyrene, 0.68 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under a nitrogen gas flow at 60° C. for 6 hours. After cooling to room temperature, 50 ml of water was injected, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resultant concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 1.5 g of 1-bromo-3,6,8-tri(4-methylphenyl)pyrene as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>COCCOC.C(=O)(O)[O-].[Na+].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>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
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: COCCOC
Product: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Cl
Yield: 87.8 %

Procedure:
A mixture of 7-chloro-2-iodo-thieno[3,2-b]pyridine-6-carbonitrile (1.00 g, 3.12 mmol), 4-formylphenylboronic acid (936 mg, 6.24 mmol) and 108 mgs of tetrakis(triphenylphosphine)palladium(0) in 30 mL of ethylene glycol dimethyl ether and 25 mL of aqueous saturated sodium bicarbonate is heated at reflux for 4 hours. The mixture is cooled and the precipitate is collected by filtration washing with ethyl acetate and diethyl ether to provide 818 mg of 7-chloro-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 300-305° C.; 1H NMR (CDCl3) δ 7.93 (d, J=8 Hz, 2H), 7.96 (s, 1H), 8.03 (d, J=8 Hz, 2H), 8.87 (s, 1H), 10.1 (s, 1H), MS 298.0, 300.0 (M−H)−H.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[F:40]>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[F:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(CBr)c1F
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2[nH]ccc2c(-c2ccc3c(c2)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(-c2ccc3c(c2)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27 from (S)-methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2,3-difluorobenzene, except that the racemic mixture obtained in Step G was purified by preparative HPLC using an IC column (250 mm×30 mm I.D.; 5 um) from Chiral Technologies (West Chester, Pa., USA). The mobile phase was comprised of 80% hexanes containing 0.1% formic acid (v/v) and 20% isopropanol, operating at 42.5 ml/min, with triggered collections at 280 nm (Rt=6.80 minutes) to give (S)-2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid. (S)-2-(Tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid was then used as in Example 27, Step H to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.40 (m, 1 H), 7.25-7.17 (m, 1 H), 7.15-7.06 (m, 2 H), 7.05-6.97 (m, 2 H), 6.96-6.90 (m, 1 H), 6.28 (dd, J=3.6, 12.4 Hz, 1 H), 5.69-5.62 (m, 1 H), 5.61-5.51 (m, 2 H), 4.32-4.25 (m, 2 H), 2.95-2.79 (m, 2 H), 2.78-2.72 (m, 3 H), 2.14-2.04 (m, 2 H), 1.01-0.92 (s, 9 H); LC/MS (m/z) ES+=521.39 (M+1).
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:8][OH:9].[ClH:10]>CCOCC>[ClH:10].[C:1](=[NH:7])([O:9][CH3:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: CO
Reactant: C=CCCCC#N
Agent: Cl
Solvent: CCOCC
Product: C=CCCCC(=N)OC

Procedure:
Through a stirred solution of 5-hexenenitrile (3 g, 31Mmol) and MeOH (35 mmol) in Et2O (30 ml), at 0° C., HCl gas was bubbled for 10 minutes. Solvent was evaporated in vacuo and the residue treated with Et2O to give 5.1 g of the title compound as white solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CS(O[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN1CCCC1=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 443 mg; 1.30 mmol), 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (Intermediate 43; 400 mg; 1.93 mmol), Cs2CO3 (1.30 g; 3.99 mmol) in DMF (10 mL) was stirred at 90° C. overnight. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 285 mg (48%) of the title compound as a brown solid, which was used directly used without further purification.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.N1CC[O:21]CC1.[F:24][C:25]([F:29])=[C:26](F)F.C(=O)([O-])O.[Na+]>C(#N)C>[F:24][CH:25]([F:29])[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:21]
Reactant: FC(F)=C(F)F
Reactant: C1COCCN1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 13 h
Yield: 76 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.64 g, 2.5 mmol) and morpholine (0.48 g, 5.5 mmol) in acetonitrile (5 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 13 hours. After cooling to an ambient temperature, the reaction solution was poured intoa saturated aqueous sodium hydrogen-carbonate solution (50 ml), and extracted twice with toluene (50 ml×2). The toluene layer was washed twice with 5% hydrochloric acid (30 ml×2) and water (50 ml) and then brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.64 g, 1.9 mmol, yield 76%).
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@@H:13]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C.Cl[Sn](Cl)(Cl)Cl.ClC(Cl)C>>[C:16]([O:15][C@@H:14]1[C@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:35][C@H:13]1[N:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1nc[nH]c(=O)n1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Nc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1

Procedure:
U.S. Pat. No. 3,819,780 discloses a process which involves reacting a bis-silyl compound of 5-Azacytosine with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose in the presence of SnCl4 and absolute dichloroethane to give 5-azacytidine tribenzoate, which is further reacted with methanolic ammonia to give 5-azacytidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:18][C:19]#[N:20])[C:12]=3[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(C)=O.[CH3:27]I.[C:29](=O)([O:33]CC)[O:30][CH2:31][CH3:32]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([C:19]#[N:20])([CH3:27])[C:29]([O:30][CH2:31][CH3:32])=[O:33])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Reactant: CI
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Reaction time: 1 h

Procedure:
1-(4-Chlorophenyl)isoquinoline-5-acetonitrile (2.6 g) was dissolved in 20 ml of diethyl carbonate, and 1.0 g of 50% oily sodium hydride was added. Then, 10 ml of dimethylsulfoxide was added, and 1.5 g of methyl iodide was added under cooling with water. The mixture was stirred for 1 hour. The reaction mixture was poured into water, extracted with ether, and dried. The solvent was distilled off. The resulting oily product was recrystallized from ether-hexane to afford ethyl 2-[1-(4-chlorophenyl)isoquinolin-5-yl]-2-cyanopropionate as colorless prisms having a melting point of 92° to 93.5° C.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:6][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CC/C=C/CO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC=CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.8 %

Procedure:
Trans-2-penten-1-ol (49.6 ml; 487.6 mmol) and (4-chloro-phenyl)-acetic acid (83.2 g; 487.6 mmol) were dissolved in 1200 ml of dichloromethane. After addition of EDC (140.2 g, 731 mmol) and DMAP (11.9 g, 97.5 mmol), the reaction mixture was stirred for 18 hours at room temperature. After evaporation under reduced pressure, the residue was dissolved with diethyl ether, washed with water, brine and dried over anhydrous sodium sulfate. Evaporation gave 136 g of an yellow oil, which was further purified by flash-chromatography (silica gel; hexane/ethyl acetate 9:1). Yield: 68 g (59%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[NH:13][C:12](=[O:24])[C@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:12](=[O:24])[C@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)[C@H]1CC1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere 59 mg (1.4 mmol) sodium hydride were added at 0° C. to 0.50 g (1.2 mmol) (2R)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-3-oxopiperazine-1-carboxylate (isomer 3.1) in 20 ml DMF. After 20 min at 0° C. 0.13 ml (1.4 mmol) methyl bromoacetate were added and the mixture was stirred for 30 min at 0° C. Then the reaction mixture was stirred for 5 h at RT. The reaction mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were dried and evaporated down.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Na+].[NH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[S:8][C:7]=1[C:18]([NH2:20])=[O:19]>C(O)(=O)C.O>[NH2:1][C:2]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[S:8][C:7]=1[C:18]([NH2:20])=[O:19])=[O:3]
Reactant: NC(=O)c1sc(-c2ccc(F)cc2)cc1N
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cc(-c2ccc(F)cc2)sc1C(N)=O
Reaction time: 20 h
Yield: 13.2 %

Procedure:
Sodium isocyanate (1.08 g) was added portionwise to a stirred suspension of 3-amino-5-(4-fluorophenyl)-2-thiophenecarboxamide (3.2 g) in acetic acid (150 mL) and water (90 mL). After 20 h, the solid was filtered off and washed with water, methanol and ether. Recrystallisation from methanol/dimethylsulphoxide gave the title urea (0.5 g) as a 1:1 dimethylsulphoxide solvate.