Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[C:23](Br)=[C:22]([N+:25]([O-:27])=[O:26])[C:21]([Br:28])=[N:20]3)[CH:13]=2)[N:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(O)CC>[CH2:29]([NH:36][C:23]1[N:19]([CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:4]3[C:5]([NH:4][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([Br:1])=[N:3]3)[CH:13]=2)[N:20]=[C:21]([Br:28])[C:22]=1[N+:25]([O-:27])=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3Br)c2)c1Br
Solvent: O
Solvent: CCCO
Product: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3NCc3ccccc3)c2)c1NCc1ccccc1

Procedure:
13.9 g of 1,3-bis-(3,5-dibromo-4-nitropyrazol-1-yl-methyl)benzene from step 4.1 are heated together with 6.5 g of benzylamine in 130 ml of n-propanol for 2 hours at 95° C. Subsequently the reaction mixture is cooled and poured into 400 ml water. The precipitate is filtered with suction and recyrstallized from 150 ml of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=3)=[CH:32][C:31]=2[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.O1CCOCC1.CO>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([C:43]([F:44])([F:45])[F:46])[CH:37]=3)=[CH:32][C:31]=2[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(Cl)c(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2-c2ccnnc2)cc1F
Temperature: 50 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
5-Chloro-4-(4′-chloro-3-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 57, 135 mg, 0.17 mmol) was dissolved in a 4M solution of HCl in dioxane (5 mL), methanol (5 mL) added and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was evaporated and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of dichloromethane:methanol:acetic acid 100:0:0 to 95:4:0.4 to give the title compound (75 mg, 68%) as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].CC(S)C.[CH3:11][CH:12]([S:14][C:15]1[C:16](C(O)=O)=[N:17][C:18]([S:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=1)[CH3:13]>CN(C=O)C>[CH3:24][CH:22]([S:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][CH:12]([CH3:13])[CH3:11])=[CH:16][N:17]=1)[CH3:23]
Reactant: CC(C)Sc1ccc(SC(C)C)c(C(=O)O)n1
Agent: CC(C)(C)[O-]
Agent: CC(C)S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(SC(C)C)nc1
Temperature: 50 °C

Procedure:
To 198 g of t-BuOK dissolved in 300 ml of DMF was added 2-propanethiol (163.47 ml) dropwise with an ice bath employed to keep the temperature below 50° C. As salt began to precipitate out an additional 50 ml of DMF was added. After addition was complete, the ice bath was removed and the mixture heated to 50° C. A solution of 100 g of methyl 3,6-dichloro-pyridine-2-carboxylate dissolved in DMF was added and the temperature during addition rose to 115° C. The temperature was then maintained at approximately 105°-110° C. until addition was completed and then the resulting mixture was heated at 100°-110° C. for 11/2 hrs. The reaction mixture was allowed to cool and the solvent removed in a rotary evaporator. The brown residue which remained was washed with ether and then dissolved in water. The solution was acidified with HCl, and the product, which oiled out, extracted with CH2Cl2. The CH2Cl2 was then removed using a rotary evaporator. Infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid had formed. The 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid was decarboxylated employing a Kugelrohr distillation apparatus, and 2,5-bis((1-methylethyl)thio)pyridine obtained, b.p. 310° C. (760 mm Hg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1ccnc2cc(-c3ccc(O)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Yield: 55.9 %

Procedure:
A solution of 90 mg (0.32 mmol) of methyl 7-(4-hydroxyphenyl)-4-quinolinecarboxylate, 196 mg (0.64 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 178 mg (1.29 mmol) of K2CO3 in 2.5 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 98 mg (56%) of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-quinolinecarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J=4 Hz, 1H), 8.81 (d, J=9 Hz, 1H), 8.29 (s, 1H), 7.88-7.85 (m, 2H), 7.64 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.32 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.79 (s, 2H), 4.05 (s, 3H), 3.34 (septet, J=7 Hz, 1H), 1.43 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1C=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2.IC1C=C2C(=CC=1)N(C1N=CC=CN=1)[N:32]=C2>>[CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:15]=[CH:16][CH:17]=[CH:18][N:32]=1)[N:9]=[CH:8]2
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Reactant: Ic1ccc2c(cnn2-c2ncccn2)c1
Product: CC(N)C(Oc1ccc2c(cnn2-c2ncccn2)c1)c1ccccc1

Procedure:
Prepared as described for 118a using 5-Iodo-1-pyrimidin-2-yl-1H-indazole (120b). Yield 66 mg (20%).
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[N:26]1([C:30]([C:32]2[CH:37]=[CH:36][C:35](F)=[C:34]([F:39])[CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1.[CH3:40][O:41][C:42]([C:44]1[CH:54]=[C:53]([OH:55])[C:47]2[CH2:48][C:49]([CH3:52])([CH3:51])[O:50][C:46]=2[CH:45]=1)=[O:43]>>[CH3:40][O:41][C:42]([C:44]1[CH:54]=[C:53]([O:55][C:35]2[CH:36]=[CH:37][C:32]([C:30]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])=[CH:33][C:34]=2[F:39])[C:47]2[CH2:48][C:49]([CH3:52])([CH3:51])[O:50][C:46]=2[CH:45]=1)=[O:43]
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2F)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from azetidin-1-yl-(3,4-difluoro-phenyl)-methanone (32a) (90 mg, 0.46 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (117 mg, 0.53 mmol) to give a pale yellow oil (106 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=10.86, 2.02 Hz, 1 H) 7.38-7.42 (m, 1 H) 7.21 (d, J=1.01 Hz, 1 H) 7.09 (d, J=1.01 Hz, 1 H) 6.99 (t, J=8.21 Hz, 1 H) 4.30-4.40 (m, 2 H) 4.20-4.29 (m, 2 H) 3.86 (s, 3 H) 2.97 (s, 2 H) 2.33-2.43 (m, 2 H) 1.50 (s, 6 H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[N:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[CH:17]1([Mg]Cl)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>CCOCC>[Cl:6][C:7]1[C:8]([C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:11])=[CH:12][CH:13]=[C:14]([CH3:16])[N:15]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CCCCC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
A tetrahydrofuran (30 ml) solution of 2-chloro-6-methylnicotinic acid (3.43 g, 20 mmol) was cooled to -40° C., mixed with ether (30 ml) solution of 2.0 M cyclohexyl magnesium chloride and stirred overnight at room temperature. The reaction solution was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-3-cyclohexylcarbonyl-6-methylpyridine (650 mg, 14%) as a brown oily material.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[I:26]I>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH:17]([I:26])[C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: II
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C(I)[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
6.88 g (20 mmol) of 17β-acetoxy-1α-methyl-androst-4-en-3-one and 1.75 g (22 mmol) of CuO in 60 ml of acetic acid are mixed with stirring at room temperature with 5.58 g (22 mmol) of iodine and stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, the acetic acid is largely distilled off and the residue is taken up in 100 ml of water. The water phase is extracted 3 times with 100 ml of ethyl acetate each. The ethyl acetate phases are washed with sodium thiosulfate solution and dried on sodium sulfate. After concentration by evaporation of the solution, 10 g of crude product is obtained. Recrystallization from ethyl acetate yields 8.8 g of 17β-acetoxy-2-iodo-1α-methyl-androst-4-en-3-one (93% of theory) of melting point 102° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].II>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]1[S:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(Br)ccc1Br
Agent: II
Solvent: CN(C)C=O
Product: Brc1ccc(Br)c(-c2nc3ccccc3s2)c1

Procedure:
5 g (18.5 mmol) of 2,5-dibromobenzaldehyde, 3 mL (27.7 mmol) of 2-aminothiophenol, and 2.35 g (9.25 mmol) of iodine (I2) were dissolved in 100 mL of DMF. The solution was reacted at 100° C. for 1 hour. The acquired reactant was purified through a column, obtaining 4.64 g (Y=68%) of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:43][N:44]([CH3:53])[CH2:45][CH2:46]CN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN(C)CCO>O1CCCC1.C(OCC)(=O)C>[CH3:43][N:44]([CH3:53])[CH2:45][CH2:46][O:2][C:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)O)cc2)c1=O)C(=O)C(F)(F)F
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)OCCN(C)C)cc2)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-[3-(4-carboxybenzyloxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.281 g) in dry tetrahydrofuran (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,141 g), 1-hydroxybenzotriazole hydrate (0,066 g) and 2-dimethylaminoethanol (0.06 mL). The reaction mixture was stirred overnight before it was diluted with ethyl acetate, washed (twice with saturated sodium bicarbonate solution, then brine), dried and evaporated before purification by chromatography, eluting with dichloromethane:methanol (97:3), to afford the title compound; TLC: Rf =O.18, dichlormethane:methanol (97:3); HPLC: tR =6.51, FR=1, column A, water:acetonitrile (3:2); MS: m/z=645(M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:13][CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:4]1[S:3][C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCc1sc(Br)nc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1ccccc1
Yield: 42.2 %

Procedure:
A solution of 2-bromo-5-ethyl-4-phenyl-1,3-thiazole (4.00 g, 14.9 mmol), tert-butyl piperazine-1-carboxylate (8.33 g, 44.7 mmol) and potassium carbonate (2.06 g, 14.9 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 13 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (2.35 g, 42.2%) as an oil.
Reaction SMILES: [K+].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a stirred bright orange solution of N-(4'-chloro-5'-methyl-2'-nitrophenyl)glycine potassium salt (0.097 g, 0.36 mmol) in water (5.0 mL) at 80° C., sodium dithionite (0.500 g, 2.87 mmol) was added in two equal portions. It instantly formed a white suspension, which was stirred at 80° C. for 1 h. It was then cooled at room temperature and the solid was vacuum filtered, washed with water (5.0 mL), and dried in vacuo to yield 0.062 g (86%) of the title compound as a white powder; 1H NMR (DMSO-d6): δ2.10 (s, 3H), 3.66 (s, 2H, J=1.2 Hz), 5.98 (s, 1H), 6.53 (s, 1H), 6.67 (s, 1H), 10.20 (s, 1H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][N:20](COCC[Si](C)(C)C)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8].C1COCC1.C(O)C.[OH-].[NH4+]>Cl.O>[CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8]
Reactant: CSCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CSCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 50.7 %

Procedure:
A solution of 5-(methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 3.0 M HCl (HCl) in water (4 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a pale orange oil. The oil was stirred in ethanol (3 mL, 0.05 mol) and 8.0 M ammonium hydroxide in water (1 mL) overnight. The reaction was concentrated and purified by prep LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give 125 mg of a white foam. The white foam was triturated with MTBE (˜1.5 mL). The resulting solid was filtered, washed and dried to give 80 mg of the product (32% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][C@H:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][C@@H:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of (S)-3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxylprop yl)benzamide (400 mg, 1.23 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (123 mg, 1.23 mmol). The mixture was stirred at 25° C. for 2 h. NaBH3CN (387 mg, 6.15 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (160 mg, Yield 31.8%). 1H NMR (CD3OD, 400 MHz): δ 7.94-7.76 (m, 2H), 7.63-7.56 (m, 1H), 7.56-7.49 (m, 1H), 7.32-7.24 (m, 3H), 7.21-7.15 (m, 1H), 4.71-4.55 (m, 1H), 4.52-4.28 (m, 2H), 4.05-3.95 (m, 2H), 3.92-3.70 (m, 2H), 3.62-3.46 (m, 3H), 3.46-3.33 (m, 4H), 3.28-3.02 (m, 2H), 1.99-1.85 (m, 2H), 1.82-1.66 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.N1CCNCC1.C(Cl)(=O)C1C=CC(OC)=CC=1.Cl[CH2:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:37].N1CCOCC1.ClCC(Cl)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:35][C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1
Reactant: O=C(CCl)N1CCOCC1
Agent: C1CNCCN1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: O=C(Cl)CCl
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)cc1

Procedure:
The N-(4-methoxybenzoyl)-piperazine used as a starting substance was obtained as a viscous oil by reacting 1 mol of piperazine with 0.5 mol of anisic acid chloride in glacial acetic acid. The chloroacetic acid morpholide used as a starting substance was obtained as a colourless oil by reacting 2 mol of morpholine with 1 mol of chloroacetyl chloride in toluene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[CH3:12])[N:5]=[C:4](SC)[N:3]=1.O[O:31][S:32]([O-:34])=O.[K+].[C:36](#N)C>O.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[CH3:12])[N:5]=[C:4]([S:32]([CH3:36])(=[O:34])=[O:31])[N:3]=1
Reactant: O=S([O-])OO
Reactant: CC#N
Reactant: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2cscn2)n1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1cscn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round-bottomed flask was added a mixture of (S)-4-amino-6-((1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (22 mg, 0.052 mmol) in acetonitrile (7 mL) and water (7 mL). The reaction mixture was cooled to 0° C. and Oxone (80 mg, 0.130 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and was then allowed to warm to RT. After 1.5 hours the reaction mixture was diluted with EtOAc and washed with H2O (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C19H18N8O2S2, 455; found 455.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: C1=COCCC1
Reactant: OCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.8 %

Procedure:
To a solution of 5.8 g (42 mmol) of 3-bromopropanol prepared in step B and 3.5 g (42 mmol) of dihydropyran in 15 mL of methylene chloride is added 20 mg (0.116 mmol) of p-toluenesulfonic acid, and the reaction mixture is stirred at room temperature for 7 hours, then washed with 10% NaOH solution and brine, dried, and evaporated to dryness to give 8.7 g of title product in 96% yield.