Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C1C=C(S([O:16][CH2:17][C@:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:30][C:31](=[O:39])[CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=O)=O)C=CC=1)=O)C#C.[CH2:69]([O:72][C:73]1[CH:78]=[C:77]([CH3:79])[C:76]([S:80](Cl)(=[O:82])=[O:81])=[C:75]([CH3:84])[CH:74]=1)[C:70]#[CH:71].OC[C@](O)(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN1CCOCC1)CCC1C=CC=CC=1)CC(C)C)CC1C=CC=CC=1)CC(C)C>>[CH3:79][C:77]1[CH:78]=[C:73]([O:72][CH2:69][C:70]#[CH:71])[CH:74]=[C:75]([CH3:84])[C:76]=1[S:80]([O:16][CH2:17][C:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31](=[O:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:82])=[O:81]
Reactant: C#CCNC(=O)c1cccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c1
Reactant: C#CCOc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Product: C#CCOc1cc(C)c(S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c(C)c1

Procedure:
Prepared in a similar manner to compound 13, except from 4-(propargyloxy)-2,6-dimethylbenzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=2)[CH2:3][CH2:2]1.O1CCOCC1.[NH3:19]>CCOCC>[CH:1]1([NH:4][C:5]2[N:6]=[C:7]([Cl:12])[N:8]=[C:9]([NH2:19])[N:10]=2)[CH2:2][CH2:3]1
Reactant: Clc1nc(Cl)nc(NC2CC2)n1
Reactant: N
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1nc(Cl)nc(NC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
138 g of 2-cyclopropylamino-4,6-dichloro-s-triazine are added at a slightly elevated tmeperature and with vigorous stirring to a mixture of 675 ml of dioxane and 135 ml of ether. After cooling to room temperature, 101 ml of 25%, aqueous ammonia are added dropwise over a period of 20 minutes. The reaction mixture is heated to 50° C., stirred for 16 hours and then concentrated by evaporation under water jet vaccum. The dry riesidue is diluted with 500 ml. of water and after stirring for 1 hour at room temperature, the tiny white crystals formed are separated by filtering under suction and dried under water jet vacuum at 80° C. 217 g. of 2-cyclopropylamino-4-chloro-6-amino-s-triazine are obtained.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31]CC4C=CC=CC=4)[CH:27]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].O1CCCC1>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(OC(=O)C2CCc3cc(OCc4ccccc4)ccc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(OC(=O)C2CCc3cc(O)ccc3C2)cc1
Yield: 97.7 %

Procedure:
Then, 0.04 g of 5% palladium/carbon and 10 ml of a tetrahydrofuran solution containing 0.36 g of 2-(4-decyloxyphenyloxycarbonyl)-1,2,3,4-tetrahydro-6-benzyloxynaphthalene were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.29 g of 2-(4-decyloxyphenyloxycarbonyl)-1,2,3,4-tetrahydro-6-hydroxynaphthalene as a white crystal (isolated yield: 97%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][S:9][C:10]=1[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[C:15]([O:14][C:12]([NH:11][C:10]1[S:9][N:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1nnsc1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1snnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (0.87 g, 2.9 mmol) in a THF/ethanol mixture (18 ml; 3:1) was cooled to 0° C. and treated with lithium hydroxide (8.6 ml; 1N aqueous solution). After 15 min, the cooling bath was removed and the reaction mixture was stirred for 4 h at ambient temperature. The solvent was evaporated, and the residue was partitioned between diethylether (30 ml) and water (5 ml) and extracted. The aqueous phase was extracted with diethylether and the ether phases were washed with water. The combined aqueous phases were acidified with HCl (9 ml, 1N aqueous solution) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water, dried and the solvent was evaporated to yield the product as colorless solid (0.66 g, 94%) which was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1CO>CC(O)C>[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1[CH2:22][O:21][CH2:20][CH:19]([OH:31])[CH2:18][N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[O:32])[CH2:17][CH2:16]1
Reactant: COc1ccc(CO)c(OC)c1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: COc1ccc(COCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)c(OC)c1

Procedure:
Compound 19 was prepared in a similar manner to compound 7, substituting the commercially available 2,4-dimethoxy-benzylalcohol for 2-propanol in part C. MS (M+1)=472.42
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26])[CH:17]=[CH:16]2.[OH-].[Na+].C1COCC1.CO>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([OH:27])=[O:26])[CH:17]=[CH:16]2
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OC(Cc3ccccc3)C(=O)O)ccc2c1

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl 2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.200 g, 0.433 mmol), prepared in the previous step, and 1N NaOH (0.65 mL, 0.65 mmol) in 1.5:1.5:1 THF:MeOH:water (40 mL) with the exception that this reaction was complete after 18 hours (overnight) at ambient temperature. The title compound was isolated as a pale-yellow solid (0.194 g, 100%) and used without further purification, mp 171–173° C. Elemental Analysis for C30H25NO3.0.05 H2O Calc'd: C, 80.35; H, 5.64; N, 3.12. Found: C, 80.38; H, 5.67; N, 3.00.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[N:12]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:13](=[O:28])[CH2:14][C:15]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:18]=2[S:17](=[O:27])(=[O:26])[N:16]=1)=O)C.[O-]CC.[Na+]>C(O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:12]2[CH:7]3[CH:6]([CH2:11][CH2:10][CH2:9][CH2:8]3)[C:4]([OH:3])=[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:18]=4[S:17](=[O:26])(=[O:27])[N:16]=3)[C:13]2=[O:28])=[CH:31][CH:32]=1
Reactant: CCOC(=O)C1CCCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)C2CCCCC2N1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
A solution of the crude 2-{(4-fluoro-benzyl)-[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid ethyl ester in ethanol (20 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (9.28 g, 28.64 mmol) and stirred for 16 h at 60° C. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and dried in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep Column; 0-50% ethyl acetate in hexanes) to afford the desired product, 1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-4a,5,6,7,8,8a-hexahydro-1H-quinolin-2-one (516 mg, 0.888 mmol, 12.4% over two steps), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.07-1.81 (8H, m), 2.21-2.34 (1H, m), 3.50-5.03 (3H, m), 7.11-8.03 (7H, m). LC-MS (ESI) calcd for C23H21FIN3O4S 581.03, found 582.1 [M+H+].
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([O:11]CC2C=CC=CC=2)[C:8]([O:19][CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[N:10]=[C:9]([OH:11])[C:8]([O:19][CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1
Reactant: CCCOc1ccc(CN=[N+]=[N-])nc1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1ccc(CN)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-azidomethyl-2-benzyloxy-3-propoxy-pyridine (544 mg, 2.00 mmole), 12 mL of tetrahydrofuran, and triphenylphosphine (524 mg, 2.00 mmole) then water (540 □L, 30.0 mmole) is added and this is stirred at ambient temperature overnight. The reaction mixture is evaporated to dryness in vacuo and then washed with 2:1 hexanes/ethyl acetate and filtered. This resulting solid is taken up in ethanol and hydrogenated over 10% palladium on carbon at 1 atmosphere. The reaction mixture is filtered washed with ethanol, evaporated to give a brownish green solid, 93 mg, (25%), MS (ES+): m/z 183.3 (M+H). This is used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].[CH2:25]([NH2:27])[CH3:26]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:20][NH:27][CH2:25][CH3:26])([OH:19])[C:21]([F:24])([F:22])[F:23])=[O:15]
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Reactant: CCN
Solvent: CC#N
Product: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Yield: 101.4 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carb oxamide (2 g, 5.8 mmol) in acetonitrile (25 ml) was added ethylamine (5 ml, 23 mmol). The solution was stirred at room temperature for 24 hours under nitrogen before further ethylamine (2 ml) was added. The solution was concentrated under reduced pressure to give the title compound (2.290 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([O:13]CC)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:9])([F:8])[F:10])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(Cl)nc1C(F)(F)F
Yield: 73.5 %

Procedure:
A mixture of 116 g (0.4468 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate, 18 g (0.45 mole) of sodium hydroxide, 200 ml. of water, 400 ml. of tetrahydrofuran was stirred at room temperature for 16 hours and made acidic with 50 ml. of concentrated hydrochloric acid. The reaction mixture was extracted twice with 200 ml. of ether. The ether-tetrahydrofuran solution was dried (MgSO4) and concentrated under reduced pressure. The residual oil was treated with benzene and the benzene solution was concentrated under reduced pressure to remove the last trace of water. The residual solid was recrystallized from hexane-benzene to give 76 g (73.4%) of 2-chloro-4-trifluoromethyl-5-thiazolecarboxylic acid, m.p. 131°-131.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH3:14])[O:9][N:8]=1)[CH2:4][CH2:5][CH3:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1>C1COCC1>[CH2:3]([C:7]1[C:11]([CH2:12][O:13][C:19]2[N:18]=[N:17][C:16]([Cl:15])=[CH:21][CH:20]=2)=[C:10]([CH3:14])[O:9][N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1noc(C)c1CO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a stirred suspension of NaH (258 mg of a 55% dispersion in mineral oil) in THF (9 mL) at 0° C. under argon, was added a solution of (3-butyl-5-methyl-isoxazol-4-yl)-methanol (1.0 g, 5.9 mmol) in THF (18 mL) dropwise. The reaction mixture was warmed to room temperature. After 30 min the reaction mixture was cooled to 0° C. and a solution of 3,6-dichloropyridazine (908 mg, 6.1 mmol) in THF (18 mL) was added dropwise. After 16 h the reaction mixture was warmed to room temperature then quenched with water and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated then purified by chromatography (silica, 10 to 60% ethyl acetate in heptane) to give the title compounds (1.31 g, 66%) as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=O)[N:5]=[C:4]2[C:18]([CH3:21])=[N:19][O:20][C:3]=12.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>C(O)(C)C>[Cl:1][C:2]1[C:3]2[O:20][N:19]=[C:18]([CH3:21])[C:4]=2[N:5]=[C:6]2[C:7]=1[N:8]1[CH2:9][C@@H:10]([CH3:15])[O:11][C@@H:12]([CH3:14])[C@@H:13]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:16]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)nc12
Solvent: CC(C)O
Product: Cc1noc2c(Cl)c3c(nc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 80 °C
Reaction time: 120 h
Yield: 42.7 %

Procedure:
Isopropanol (12 ml) was added to 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-methylisoxazolo[4,5-b]pyridine-5-carbaldehyde (Intermediate 471, 165 mg, 0.53 mmol) to give a yellow slurry; pyrimidine-2,4,6(1H,3H,5H)-trione (barbituric acid) (68.2 mg, 0.53 mmol) was added, and the mixture was heated to 80° C. After about 5 days, the mixture was concentrated. The crude was purified by chromatography using 10-50% EtOAc/CH2Cl2 to give 95 mg yellow solid which was subsequently recrystallized from EtOAc/hexanes. A total of 57 mg (19%) of the title product was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:28]#[N:29])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu-]=O.CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][C:2]2[C:3]([C:28]#[N:29])=[C:4]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=3)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[CH:33][CH:32]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Br)c2C#N)ccn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Sc3ccc(Cl)cc3)c2C#N)ccn1
Yield: 75.9 %

Procedure:
N-(4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide (0.2601 g, 0.5495 mmol), copper(I) oxide (0.1572 g, 1.099 mmol), 4-chlorobenzenethiol (0.3179 g, 2.198 mmol) and potassium carbonate (0.2278 g, 1.648 mmol) were added to a microwave vial followed by DMF (15.00 mL). The reaction was irradiated at 150° C. for 15 mins. The solid was filtered and washed with DCM. The solution was diluted with 80 ml water, and extracted with 100 ml DCM for two times. The organic layer was concentrated, and purified by column. The eluent was 50-100% ethyl acetate in hexane to yield a solid product (0.224 g, yield 76.0%) LCMS: (AA) ES+ 537, 539. 1H NMR (300 MHz, CDCl3) δ: 8.59 (s, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.53 (d, 1H), 7.32 (d, 2H), 7.22 (d, 2H), 5.50-5.55 (dd, 1H), 4.02-4.08 (m, 1H), 3.68-3.78 (m, 1H), 2.25 (s, 3H), 2.10-2.18 (m, 1H), 2.00-2.07 (m, 2H), 1.66-1.80 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[C:16]([Cl:25])[CH:15]=3)=[CH:12][C:11](C(O)=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C2N(C3C=NC=CC=3)N=C([C:52]3[C:57]4[CH2:58][NH:59][C:60](=[O:61])[C:56]=4[CH:55]=[CH:54][N:53]=3)C=2)C=C(OC(F)(F)F)C=1.NC1C=CNN=1.BrC1C=CNN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[C:16]([Cl:25])[CH:15]=3)=[CH:12][C:11]([C:52]3[C:57]4[CH2:58][NH:59][C:60](=[O:61])[C:56]=4[CH:55]=[CH:54][N:53]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1NCc2c1ccnc2-c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Brc1cc[nH]n1
Agent: Nc1cc[nH]n1
Product: O=C1NCc2c1ccnc2-c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The synthesis is prepared from 825 mg (1.90 mmol) of the compound from example 9A in a manner analogous to the synthesis of the compound from example 6. This produces 844 mg (81% of theoretical yield) of trimethylsilyl ethyl carbamate (step 1), 541 mg (87% of theoretical yield) of aminopyrazole (step 2) and 223 mg (37% of theoretical yield) of bromopyrazole (step 3). In step 4, 30 mg (27% of theoretical yield) of the title compound are obtained from 100 mg (0.21 mmol) of the compound from step 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@H]1CCCC[C@@H]1N>O1CCOCC1.O.CCOC(C)=O.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:20]2[CH:21]=[CH:22][C:18]([CH3:17])=[N:19]2)[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1OCc1ccccc1
Reactant: Cc1cc[nH]n1
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn(-c2ccc(F)c(OCc3ccccc3)c2)n1
Temperature: 200 °C
Yield: 23 %

Procedure:
To a microwave vial containing 2-benzyloxy-4-bromo-1-fluoro-benzene [CAS: 1036724-54-5](1500 mg, 5.34 mmol) and 3-methyl-1H-pyrazole (525.68 mg, 6.4 mmol) in 1,4-dioxane (10 mL) was added copper (I) iodide (101.62 mg, 0.5300 mmol), potassium phosphate (2265.26 mg, 10.67 mmol), and (1S,2S)-(+)-1,2-diaminocyclohexane (60.93 mg, 0.5300 mmol). The vial was sealed and heated in a microwave at 200° C. for 2 h 30 minutes. The reaction was diluted with water (50 mL) and EtOAc (30 mL), and the organics were separated, washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (50 g, SNAP cartidge), eluting with a gradient of EtOAc:isohexane from 0% to 30%. Fractions containing the first eluting product were combined and concentrated in vacuo to give 1-(3-benzyloxy-4-fluoro-phenyl)-3-methyl-pyrazole (D66) (385 mg, 1.2274 mmol, 23% yield) as a colourless oil which crystallised on standing;
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([F:15])=[C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][NH2:26]>O1CCOCC1>[F:8][C:7]1[C:2]([NH:25][NH2:26])=[N:3][C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:5]([F:15])[C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: NN
Reactant: Fc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Solvent: C1COCCO1
Product: NNc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Temperature: 100 °C

Procedure:
4-[2,3,5-Trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine (1.2 g; 3.5 mmol) and hydrazine (2 g) were added to dioxane (10 mL) and heated to 100° C. for six hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (20 mL) and washed with a 10% sodium carbonate solution (2 mL). It was dried over magnesium sulfate, and evaporated, to give crude [3,5-Difluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl -ethoxy)-pyridin-2-yl]-hydrazine. The crude product was then dissolved in ethanol. To the solution was added one drop of acetic acid, and m-tolylaldehyde (600 mL; 5 mmol) and it was heated at 60° C. overnight. The solvent was then evaporated, and the residue was purified by column chromatography to give Compound 12 (850 mg). Theoretical Mass Ion: 461.1; observed MH+ peak: 462.1.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18](OC)=O)[NH:15]2)=[CH:11][CH:10]=1>O1CCOCC1>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH3:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc2cc(C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a suspension of LiAlH4 (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL) at 0° C. After the addition, the mixture is stirred at room temperature for 1 h and then heated at reflux for 5 h. After cooling to 0° C., the reaction is quenched by water (dropwise) and then 15% aqueous NaOH. After stirring at room temperature for 1 h, the mixture is filtered through Celite. The solid is washed with a large amount of EtOAc. The solvent is washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue is purified by flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 61% of 6-methoxy-2-methyl-1H-indole.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][C:61]=1[CH3:69]>>[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][C:61]=1[CH3:69]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(C)c4)cc3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 161 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-fluoro-3-methyl benzoyl chloride.