Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[S:6])=S.CI.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:13]=1[CH2:14][NH2:15]>CO.C(O)C>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:14][NH:15][C:2](=[NH:1])[NH:4][C:5]([NH2:7])=[S:6]
Reactant: NC(=S)NC(N)=S
Reactant: COc1cccc(OC)c1CN
Solvent: CI
Solvent: CCO
Solvent: CO
Product: COc1cccc(OC)c1CNC(=N)NC(N)=S
Temperature: 5 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
2.00 g (14.8 mmol) dithiobiuret were placed in 25 ml methanol and 2.10 g (14.8 mmol) methyliodide were added at room temperature. The mixture was heated for 3 hours at reflux, then the solution was concentrated, was diluted with 25 ml of ethanol and 2.47 g (14.8 mmol) 2,6-dimethoxybenzylamine were added. The mixture was subsequently stirred again for 2 hours at reflux and subsequently for 30 minutes at 5° C. Filtration of the precipitate formed yielded 970 mg N-[[(2,6-dimethoxybenzyl)amino](imino)methyl]thiourea.
Reaction SMILES: O[CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[CH:4]1.CN(C)C=O.S(Cl)([Cl:17])=O>C(Cl)(Cl)(Cl)Cl>[Cl:17][CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[CH:4]1
Reactant: OCn1cnc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: ClCn1cnc(Cl)c1Cl
Yield: 77.1 %

Procedure:
94 g of 1-hydroxymethyl-4,5-dichloroimidazole is dissolved in 550 ml of carbon tetrachloride. 1 ml of dimethylformamide is added, and 100.5 g of thionyl chloride is dripped in while stirring. The mixture is refluxed until no more gas evolves, after which the solvent is removed under reduced pressure and 750 ml of methylene chloride and 250 ml of water are added to the residue. While the mixture is stirred thoroughly, its pH is brought to 7.5 with 5% strength aqueous sodium hydroxide solution. The organic phase is then separated, washed with water and dried over sodium sulfate. The residue remaining after removal of the solvent is distilled at 92° to 95° C./0.1 mbar. There is obtained 80.5 g (77%) of 1-chloromethyl-4,5-dichloroimidazole; m.p.: 40°-41° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:16][C:15]=1[F:25].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:16][C:15]=2[F:25])[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CCS(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OC)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of (5-chloro-2-methoxyphenyl)boronic acid (714 mg, 1.68 mmol) in dioxane (5 mL) and water (1 mL) was added 1-bromo-4-(ethylsulfonyl)-2-fluorobenzene (Preparation 19, 450 mg, 1.68 mmol), and sodium carbonate (534 mg, 5.04 mmol). The reaction was degassed and then tetrakis(triphenylphosphine) palladium(0) (194 mg, 0.17 mmol) was added and the reaction mixture further degassed. The reaction was placed on a preheated hot plate (110° C.) for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:cyclohexane 40:60 to give the title compound as a brown oil in 90% yield, 500 mg.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[N:13])[C:9]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[S:16][C:8]=2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>C[O-].[Na+].CO>[C:12]([C:10]1[C:9]2[N:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[S:16][C:8]=2[C:7]([OH:24])=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[N:11]=1)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2nc(-c3ccc(F)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 4-cyano-2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (67 mg, 0.19 mmole) and glycine (875 mg, 11.66 mmole) in 0.5 M sodium methoxide/methanol (9.7 ml) was refluxed for 22 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (50 ml) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (12 ml). The suspension was extracted with ethyl acetate. The organic layer was washed with water and dried in vacuo to give the title compound as a yellow solid (59 mg). MS: (+) m/z 373.24 (M+1).
Reaction SMILES: NC1N=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=CC=1.[CH3:21][C@@H:22]1[CH2:27][N:26]([C:28]2[CH:29]=[N:30][C:31]([N+:34]([O-])=O)=[CH:32][CH:33]=2)[C@@H:25]([CH3:37])[CH2:24][N:23]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[NH2:34][C:31]1[N:30]=[CH:29][C:28]([N:26]2[C@@H:25]([CH3:37])[CH2:24][N:23]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:22]([CH3:21])[CH2:27]2)=[CH:33][CH:32]=1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: C[C@@H]1CN(c2ccc(N)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 82.7 %

Procedure:
Following the procedures as described for compound 101h, reaction of 122a (1.5 g, 4.46 mmol) afforded 122b as a yellow solid (1130 mg, 83%). LCMS: [M+H]+ 307
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]2[C:6](=[O:24])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12](=[O:23])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]2[C:6](=[O:24])[C:7]3[C:14](=[O:15])[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:23])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)cc(Cl)c3c(=O)c2C(=O)N1Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2c(Cl)cc(Cl)cc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
6,8-Dichloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0.60 g, 1.60 mM) was stirred in methanol (200 mL) and methanesulfonic acid (20 mL) was added with cooling, maintaining the temperature below 20° C. The resulting orange solution was stirred overnight at room temperature. A precipitate formed overnight and the orange suspension was heated to reflux for 1 hour. The suspension was cooled to room temperature and allowed to stand overnight without stirring. The suspension was filtered and the filtrates were slowly diluted with water (200 mL) to give a yellow suspension. This suspension was stirred for two hours and the solids were collected and washed with water, aqueous methanol, 50% methanol/ether, and ether to give the title compound (0.368 g, 61%) as a light tan powder, mp 361-363° C.; MS(CI): 374 (M+H).
Reaction SMILES: [Na][Na].[Br-].[Al+3].[Br-].[Br-].Cl.[N+:8]([C:11]1[CH:42]=[CH:41][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:17]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:43]1C=CC=CC=1>>[N+:8]([C:11]1[CH:42]=[CH:41][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:43])=[C:18]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:17]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1O
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1OC

Procedure:
Coupler (15): A mixture of 5 g of the intermediate prepared in the above procedure and 5 g of aluminum bromide was refluxed under heating in anhydrous benzene for 16 hours and then by treating the product with dilute hydrochloric acid, 4-(4-nitrophenoxy)-2-hexadecanoylaminophenol having a melting point of 96-97° C was obtained. The solvent used for the recrystallization was methanol. Then, by following the same procedure as in the synthesis of Coupler (1) in Synthesis Example 1, the desired coupler was obtained.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:7]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:5])([CH3:4])[CH3:3].[O-:34][C:35]#[N:36].[K+].O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:35]([NH2:36])=[O:34])=[CH:8][C:7]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:4])[CH3:5]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCC(CC(=O)Nc1cc(CNC(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Yield: 60 %

Procedure:
A mixture of 450 mg (0.94 mmol) of N-[2-t-butyl-5-(aminomethyl)phenyl]-3-(2,4-dimethoxyphenyl)octanamide-hydrochloride (prepared as described in Preparation 26B), 203 mg (2.50 mmol) of potassium cyanate, 30 ml of water and 1 ml of acetic acid was heated under reflux for 2 hours. At the end of this time, the reaction mixture was neutralized by adding sodium hydrogencarbonate, after which the mixture was extracted with ethyl acetate. The extract was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 37 g of silica gel using a 100:5 mixture of ethyl acetate and methanol as the eluent, to give a crystalline product. This product was recrystallized from a mixture of methylene chloride and hexane to give 273 mg of the title compound in a 60% yield, melting at 112°-113° C. (from methylene chloride-methanol). Nuclear Magnetic Resonance Spectrum (270MHz, CDCl3) δ ppm:
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C@H:6]([CH3:13])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])C.CO>[OH-].[Na+]>[CH3:13][C@H:6]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCC[C@@H](C)CC(=O)O
Yield: 87.5 %

Procedure:
300 mg. of 3(R),7-dimethyl octanoic acid ethyl ester obtained from example 14 was refluxed in 6N NaOH (1 ml.), methanol (4 ml.) for 2 hours. It was worked up as in Example 10 to give 226 mg. (87.5% yield) of R-(+)-dihydrocitronellic acid, b.p. 54°/0.4 mmHg. (Kugelrohr), [α]D25 + 6.31° (c=5.069, CHCl3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)#[N:2].C([OH:26])C>OO.[OH-].[Na+]>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:10]2[N:2]=[C:1]([OH:26])[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:9]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: CCO
Reactant: COc1cc(C(=O)Nc2ccccc2C#N)cc(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(-c2nc(O)c3ccccc3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed a solution of N-(2-cyanophenyl)-3,4,5-trimethoxybenzamide (22 g, 70.44 mmol, 1.00 equiv) in ethanol (200 mL), H2O2 (200 mL) and sodium hydroxide (200 mL, 20%). The resulting solution was stirred for 16 h at room temperature. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 500 mL of water. The solids were collected by filtration. This resulted in 12 g (55%) of 2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a white solid. MS (ESI) m/z 313 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]1[O:16][CH2:15][CH:14]2[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]2[CH2:12]1.[H][H]>CCOC(C)=O.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(C2CN3CCN(C(=O)OC(C)(C)C)CC3CO2)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1C1CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO1

Procedure:
9aS)-tert-Butyl 3-(2-methyl-3-nitrophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.45 g, 3.84 mmol) was dissolved in EtOAc (30 ml) then added 10% Pd/C (0.409 g) and stirred under a balloon of hydrogen overnight. The catalyst was filtered off and solvent evaporated to yield the title compound. LC-MS (IE, m/z): 348 [M+1]+
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:18]3[N:17]=[C:16](S)[NH:15][C:14]=3[CH:13]=[C:12]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:11]=2)=[CH:7][CH:6]=1>C(OCC)(=O)C>[F:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:18]3[N:17]=[C:16]([NH:2][NH2:3])[NH:15][C:14]=3[CH:13]=[C:12]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:11]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: NNc1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
1.0 ml of hydrazine monohydrate was added to 130 mg of 4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-1H-benzimidazole-2-thiol, and the reaction liquid was stirred overnight at 130° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:9]([OH:12])([OH:11])=[O:10])[S:5]([O-:8])(=[O:7])=[O:6])#[N:2].[H][H]>N.[Rh]>[NH2:2][CH2:1][CH2:3][CH:4]([P:9]([OH:12])([OH:11])=[O:10])[S:5]([OH:8])(=[O:6])=[O:7]
Reactant: N#CCC(P(=O)(O)O)S(=O)(=O)[O-]
Reactant: [H][H]
Agent: [Rh]
Agent: N
Product: NCCC(P(=O)(O)O)S(=O)(=O)O

Procedure:
The hydrogenation of 2-cyano-1-phosphonoethanesulfonate is carried out using the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 82, 2386 (1960)). The cyano compound (2.15 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture is hydrogenated at 40 PSI on a Parr apparatus for several hours (until uptake of hydrogen is complete). The catalyst is filtered off, and the filtrate is evaporated dry. The product is purified by dissolving the residue in water, adding ethanol to give a precipitate, and collecting the solids by filtration. Further purification is accomplished by again recrystallizing from water/ethanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Reactant: c1c[nH]cn1
Product: c1cn(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][CH2:8]Cl)=[CH:2]1.[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]=2[N:20]=1>C(Cl)(Cl)Cl>[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][N:16]([CH2:8][CH:7]=[CH:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH2:17][CH2:18][C:19]=2[N:20]=1
Reactant: ClCC=Cc1ccoc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccoc1)CC2
Yield: 30 %

Procedure:
Prepared from 3-(3-furyl)allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 30% of theory, Melting point: 130°-136° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][C:7]1[CH:16]=[C:15]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:14]2[C:9](=[CH:10][C:11]([O:42][CH3:43])=[C:12](/[CH:34]=[CH:35]/[CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[CH:13]=2)[N:8]=1)[CH3:5]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:6][C:7]1[CH:16]=[C:15]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:14]2[C:9](=[CH:10][C:11]([O:42][CH3:43])=[C:12]([CH:34]3[CH2:3][CH:35]3[CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[CH:13]=2)[N:8]=1)[CH3:5]
Reactant: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(/C=C/CC(C)(C)CO)c(OC)cc2n1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(C3CC3CC(C)(C)CO)c(OC)cc2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.67 g, 2.97 mol) and freshly prepared diazomethane (300 mL, 0.5 M solution in Et2O, 150 mmol) were added to a solution of the product from Step 3 (16.6 g, 29.7 mmol) in Et2O (300 mL) cooled to 0° C. After 15 minutes, N2 was bubbled through the mixture for 15 minutes, and the black mixture was filtered through CELITE with Et2O as the eluent. The solvent was removed in vacuo, and the residue was taken up in Et2O (300 mL) and cooled to 0° C. Palladium acetate (0.67 g, 2.97 mol) and freshly prepared diazomethane (100 mL, 0.5 M solution in Et2O, 50 mmol) were then added. After 15 minutes, N2 was bubbled through the mixture for 15 minutes, and the black mixture was filtered through CELITE with Et2O as the eluent. The solvent was removed in vacuo, and the residue was taken up in Et2O (300 mL) and cooled to 0° C. Palladium acetate (0.67 g, 2.97 mol) and freshly prepared diazomethane (100 mL, 0.5 M solution in Et2O, 50 mmol) were then added. After 15 minutes, N2 was bubbled through the mixture for 15 minutes, and the black mixture was filtered through CELITE with Et2O as the eluent. The solvent was removed in vacuo, and the crude product was purified on silica (gradient elution, 0-60% EtOAc/hexanes) to yield the title compound. LRMS ESI+ (M+H)+ 573.2, calcd for C31H45N2O8: 573.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:13]N(C=O)C.[H-].[Na+].CI>C(Cl)(Cl)Cl.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH:10]([O:12][CH3:13])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: OC1CN(c2ccc(Cl)nn2)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CN(c2ccc(Cl)nn2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(6-Chloropyridazine-3-yl)azetidin-3-ol (599 mg) was mixed with DMF (6 ml), and sodium hydride (55% suspended in oil) (211 mg) was added thereto at 0° C., followed by stirring at 0° C. for 10 minutes. Then, methyl iodide (916 mg) was added thereto at 0° C., followed by stirring at room temperature overnight. To the reaction mixture were added water, EtOAc, and CHCl3, and the organic layer was washed with water and saturated brine, then dried over anhydrous Na2CO3, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 3-chloro-6-(3-methoxyazetidin-1-yl)pyridazine (323 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[C:6]([CH2:8]O)[CH:7]=1.[Cl:24]C1N=C(Cl)N=C(Cl)N=1>CS(C)=O.CCOC(C)=O>[Cl:24][CH2:8][C:6]1[CH:5]=[C:4]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CO)c2)COC1(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CCl)c2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.1 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-fluoro-5-(hydroxymethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (330 mg, 1.014 mmol) in anhydrous DMSO (2. 028 mL) was added 2,4,6-trichloro-1,3,5-triazine (112 mg, 0.609 mmol) portionwise. The mixture was stirred at room temperature for 30 min. The mixture was diluted with EtOAc, and separated. The organic phase was washed with H2O (5×30 mL), dried over anhydrous Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified with flash chromatography eluting with 0-100% EtOAc/heptane to provide (S)-tert-butyl 4-(3-(chloromethyl)-5-fluorophenyl)-2,2-dimethyloxazolidine-3-carboxylate (329 mg, 94%). LCMS (m/z): 288.1 (MH+-56), 1.12 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.B1(C(C)=C)O[C:32](C)(C)[C:31](C)([CH3:36])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH:21]1([C:13]2[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]([CH3:36])=[CH2:32])=[CH:3][CH:4]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1ccc(-n2nc3cc(NS(C)(=O)=O)c(C4CC4)cc3c2C(=O)NC)cc1
Temperature: 95 °C
Yield: 36.2 %

Procedure:
2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) (30 mg, 0.065 mmol), 2-isopropenylboronic acid pinacol ester (37 μL, 0.20 mmol), potassium phosphate (55 mg, 0.26 mmol), tricyclohexylphosphine (3.5 mg, 0.013 mmol) and Pd(OAc)2 (2.1 mg, 0.0094 mmol) had degassed toluene (1 mL) and water (0.1 mL) added and the reaction was heated at 95° C. under argon for 5 h. The reaction mixture was concentrated to dryness and the residue was suspended in DMSO (1 mL), centrifuged, supernatant removed and purified by reverse phase flash column chromatography eluting with ACN/water (0-40-100%) affording 5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2-[4-(prop-1-en-2-yl)phenyl]-2H-indazole-3-carboxamide (ii) as a white solid (10 mg, 27%).