Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]([CH3:25])[C:22](=O)[CH3:23]>ClCCl>[CH3:9][O:10][N:11]=[C:22]([CH:21]([NH:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:12])[CH3:25])[CH3:23]
Reactant: CON
Reactant: CC(=O)C(C)Nc1c(C)cccc1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(C)C(C)Nc1c(C)cccc1C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A sample of 50.5 g triethylamine was added dropwise to a solution of 50.1 g (0.6 mol) methoxyamine hydrochloride in 75 ml dichloromethane at 9°-20° C. To the resulting solution was added about one-half of a 95.6-g (0.5-mol) sample of 3-(2,6-dimethylphenylamino)-2-butanone. The reaction temperature rose from 16° C. to 30° C. The reaction mixture was cooled in an ice bath, and the remaining 3-(2,6-dimethylphenylamino)-2-butanone was added dropwise. The reaction mixture was then stirred about 18 hours at about 20° C., washed with 50 ml of water and evaporated under reduced pressure to give 100.3 g of 3-(2,6-dimethylphenylamino)-2-butanone O-methyloxime, as an oil. The nuclear magnetic resonance spectrum showed a sharp 3-proton singlet (--OCH3) at 3.9 ppm (relative to tetramethylsilane) and a sharp 6-proton singlet (2,6-dimethyl groups) at 2.2 ppm.
Reaction SMILES: O1C2C=CC(C(Cl)=O)=CC=2OC1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[NH2:17].[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1>C1(C)C=CC=CC=1.C(O)C>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([NH:47][C:48]([NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:21][C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[C:14]([Cl:13])[CH:15]=3)=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(N=C=S)c1ccc2c(c1)OCO2
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc5c(c4)OCO5)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
1,3-Benzodioxole-5-carbonyl isothiocyanate was prepared using commercially available 1,3-benzodioxole-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,3-benzodioxole-5-carbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](=[O:13])(=[O:12])[N:9]([CH3:11])[CH3:10])[N:3]=1.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:10][N:9]([CH3:11])[S:8]([C:4]1[N:3]=[C:2]([NH:15][NH2:16])[CH:7]=[CH:6][CH:5]=1)(=[O:13])=[O:12]
Reactant: NN
Reactant: CN(C)S(=O)(=O)c1cccc(Cl)n1
Solvent: CCCCO
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc(NN)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To 12 g of 2-chloro-6-dimethylsulfamoylpyridine were added 30 ml of n-butanol and 4 g of hydrazine hydrate. The mixture was stirred at room temperature for 30 minutes, followed by heating under reflux for 18 hours. After cooling, crystals obtained were filtered and washed with water to obtain 6.1 g of 6-dimethylsulfamoyl-2-hydrazinopyridine. m.p.: 117° to 120° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[OH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS me/(%) 308 (M+H+, 100)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:40])[C:11](=[O:39])[NH:12][CH:13]([CH3:38])[CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37]>ClCCl>[Cl:1][C:19]1[N:20]([CH3:24])[C:21]2[C:17]([C:18]=1[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37])=[CH:16][C:15]([CH2:14][CH:13]([NH:12][C:11]([N:10]([CH3:9])[CH3:40])=[O:39])[CH3:38])=[CH:23][CH:22]=2
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(CC(C)NC(=O)N(C)C)cc23)c(OC)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(Cl)n(C)c3ccc(CC(C)NC(=O)N(C)C)cc23)c(OC)c1
Reaction time: 0.17 h

Procedure:
N-Chlorosuccinimide (0.437 g) was added in one portion to a stirred solution of methyl 4-[5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (1.3 g) in dry dichloromethane (25 ml), under a nitrogen atmosphere. After 10 minutes, the solvent was evaporated, and the product purified by flash chromatography, eluting with 3:7 ethyl acetate:toluene, to give, after crystallization from ethyl acetate, methyl 4-[2-chloro-5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3methoxybenzoate (45%) as a white solid; mp 148° C.; NMR (300 MHz, DMSO-d6). 0.96 (d, 3H, CH3), 2.50-2.60 (m, 1H), 2.68 (s, 6H), 2.75-2.85 (m, 1H), 3.68-3.86 (m, 7H), 3.93 (s, 3H, OCH3), 4.02 (s, 2H), 5.87 (d, 1H, NH), 6.95-7.05 (m, 2H), 7.19 (s, 1H), 7.37 (d, 1H), 7.40-7.55 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH2:23][OH:24])[C:11]1=[O:25])=[O:4].O[Li].O.Cl>C1COCC1.O.CO>[CH:16]1([CH:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:25])[C@H:12]([CH2:22][CH2:23][OH:24])[CH2:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@H](CCO)CCC1C1CCCCC1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@H](CCO)CCC2C2CCCCC2)c(C(=O)O)s1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
To a solution of 3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (123 mg, 0.28 mmol, 1 equiv.) in THF/H2O/MeOH (1.0 mL/1.0 mL/0.5 mL) was added LiOH.H2O (60 mg, 1.38 mmol, 5 equiv) and the resulting solution was stirred at 50° C. for 20 minutes. The solution was then acidified to pH=5 by addition of 3.0 N HCl aq. solution. The solution was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give product 28 mg (yield 23%). MS: 432 [M+H+]. 1H-NMR (400 MHZ, CD3OD): 6.85 (s, 1H), 3.92 (br, 1H), 3.67 (m, 2H), 2.41 (br, 1H), 2.15 (m, 1H), 1.97 (m, 2H), 1.78 (m, 7H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H).
Reaction SMILES: [OH-].[Na+].C1C(S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=C(Cl)C=1.[C:20]([OH:25])(=O)[C:21](O)=O.C[C:27]1[C:32]([OH:33])=[C:31](C)[C:30](C)=[C:29]([C:36]([C:39]2C=CC(O)=C[CH:40]=2)(C)[CH3:37])[C:28]=1C>C1(C)C=CC=CC=1.O>[C:32]1([OH:33])[CH:31]=[CH:30][C:29]([C:36]2[CH:37]=[CH:21][C:20]([OH:25])=[CH:40][CH:39]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1c(C)c(C(C)(C)c2ccc(O)cc2)c(C)c(C)c1O
Agent: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 130 °C

Procedure:
This mixture was stirred and heated under a nitrogen atmosphere. To it was added over 8 minutes at 40°-49° C. aqueous sodium hydroxide (49.47%, 36.31 g, 447.8 mmole); the contents of the addition funnel were rinsed in with a total of about 6 ml of hot deionized water. Temperature was raised over 29 minutes to 109° C. and then over 1.5 hours to 122° C. while water was periodically drained from the Dean-Stark trap. Toluene was then removed over 27 minutes, the temperature rising to 160° C. A hot solution of 4,4'-dichlorodiphenylsulfone (64.62 g, 225.0 mmole) in toluene (75 ml) was then added over 25 minutes at a reactor temperature of 160° C., and the addition funnel was rinsed with about 10 ml of hot toluene. The mixture was stirred for 4 hours at 160°-162° C., becoming very viscous. To it were added in quick succession aqueous sodium hydroxide (49.47%, 0.19 g, 2.3 mmole), hot deionized water (about 1 ml), and toluene (5 ml). The added water was readily removed by distillation. The mixture was stirred about one hour longer at 160° C., then allowed to cool overnight. On the second day, chlorobenzene (195 g) was added, and the temperature was raised to 130° C. to effect complete solution. Methyl chloride was sparged in for one hour at 111°-114° C. to endcap the polymer; then oxalic acid 1.0 g (11 mmole) was added, and the mixture was stirred for 30 minutes at 109°-111° C. The solution was filtered through a layer of filter aid on a coarse porosity fritted-glass funnel. The polymer was recovered by coagulation in a Waring blender, washed thoroughly with water and methanol, and dried in a vacuum oven at about 150° C. Yield 66.98 g (63.4%), reduced viscosity (1 g/dl in N-methylpyrrolidone at 25° C.) 0.53 dl/g. The composition of the diphenol mixture used to make this copolymer was 70 mole percent tetramethylbisphenol A/30 mole percent bisphenol. Test results on the polymer containing tetramethylbisphenol A are given in Table 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH2:25][NH2:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH2:25][NH:26][C:30](=[O:32])[CH3:31])[CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2cc3nccc(-c4cccc(CN)c4)c3o2)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-c2cc3nccc(-c4cccc(CNC(C)=O)c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 45 %

Procedure:
3-[2-(3,4,5-Trimethoxy-phenyl)-furo[3,2-b]pyridin-7-yl]-benzylamine (0.036 mmol) is dissolved in acetic acid (1.00 ml) and acetic acid anhydride (0.159 mmol) is added. The reaction solution is stirred 4 d at RT. Water is added and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The product is isolated after removal of the solvent in vacuo as yellow solid (45% yield). HPLC (method A): Rt 2.52 min (purity 99.4%); LCMS (ESI+) (method E): Rt 1.87 min, M+H+ 433.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.57 (d, J=5.1, 1H), 8.44 (t, J=5.7, 1H), 8.09 (d, J=12.1, 1H), 7.97 (d, J=7.8, 1H), 7.76 (d, J=2.8, 1H), 7.69-7.56 (m, 2H), 7.44 (t, J=9.5, 1H), 7.33 (d, J=7.8, 2H), 4.39 (d, J=5.9, 2H), 3.91 (d, J=11.1, 6H), 3.78-3.70 (m, 3H), 1.91-1.77 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:31][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[CH3:30])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
2000.0 mg (6.809 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 1417.0 mg (7.490 mmol) of 1-[3-(trifluoromethyl)phenyl]-ethanamine are placed in 10 ml of dimethylformamide and treated with 1104.0 mg (8.171 mmol) of HOBt. After 10 mins' stirring, 1697.0 mg (8.852 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1). A subsequent enantiomer separation by preparative HPLC on chiral phase [Method 14] yields 1260 mg (40% of theory) of the enantiomerically pure target compound (see also Example 80).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CSC(=Nc1nc2ncc(Br)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Brc1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (300 mg, 0.895 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (210 mg, 0.895 mmol) and cesium carbonate (600 mg, 1.79 mmol) in acetonitrile (25 mL) was heated on a 100° C. oil bath for 2 hours in an open flask, with nitrogen bubbling through the solution the entire time to help in the removal of methanethiol. After 2 hours, TLC showed the reaction to be complete, so the mixture was cooled to ambient temperature, diluted with water and concentrated in vacuo. The mixture was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (200 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.39 (br. s., 1 H) 8.48 (s, 1 H) 4.05 (d, J=9.79 Hz, 1 H) 3.72 (d, J=9.79 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.73-3.08 (m, 5 H) 2.10-2.22 (m, 2 H) 1.73-1.84 (m, J=14.09, 9.94, 4.17, 4.17 Hz, 1 H) 1.52-1.65 (m, 2 H). MS (LC/MS) R.T.=1.29; [M+H]+=394.99.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]2[N:13]=[CH:14][CH:15]=[CH:16][C:6]=2[CH2:5]1.C(OCC)C>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[N:13][C:7]2[NH:8][CH2:9][CH2:10][C:11](=[O:12])[N:4]([CH3:3])[CH2:5][C:6]=2[CH:16]=1
Reactant: CN1Cc2cccnc2NCCC1=O
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1Cc2cc(Br)cnc2NCCC1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Bromine (189 μL, 3.7 mmol) was added to a solution of 5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (460 mg, 2.4 mmol) in 10 mL of acetic acid and stirred at room temperature for 17 h. Add 30 mL of diethyl ether and collect orange solid product via suction filtration. Redissolve the solid in DCM and wash with NaHCO3, dry the organic layer over MgSO4, and concentrate in vacuo to obtain orange solid product. Yield 670 mg (quant); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.0 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 5.17 (bs, 1H), 4.49 (s, 2H), 3.59 (bm, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.85 (s, 3H); ESI MS m/z 270, 272 [C10H12N3OBr+H]+
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].Cl.[SH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1cccnc1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2cccnc2)s1
Temperature: 90 °C
Yield: 79.2 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1 g), 3-mercaptopyridine hydrochloride (1 g) and potassium carbonate (1.5 g) in N,N-dimethylformamide (10 ml) was heated at 90° C. for 4.5 hours with stirring. The reaction mixture was poured into ice water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(3-pyridylthio)thiazole (0.9 g, yield: 81.8%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8](Br)Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:14]>N1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH:8]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1C(Br)Br
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: O=Cc1ncccc1Br
Temperature: 60 °C

Procedure:
A suspension of 3-bromo-2-dibromomethyl-pyridine (10.0 g, 30.32 mmol) in morpholine (30.0 mL) was heated at 60° C. for 1 h. The reaction mixture was then cooled to rt and diluted with EtOAc (200 mL) followed by adjustment to pH 4 by adding citric acid (40.0 g). The reaction mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica (100-200 mesh) and 3% EtOAc in hexane as eluent to give 3-bromo-pyridine-2-carbaldehyde. 1H-NMR (400 MHz, CDCl3) δ ppm 10.23 (s, 1H), 8.75 (d, 1H), 8.03 (d, 1H), 7.32 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:20](=O)([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[O:21]N1C(=O)CCC1=O>O1CCOCC1.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:20](=[O:21])[O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)Nc1ccc2cc[nH]c2c1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a yellow, homogeneous solution of 1H-indol-6-amine (1.3007 g, 9.84 mmol) and DIPEA (2.58 mL, 14.76 mmol) in 1,4-dioxane (19.68 mL) under nitrogen was added 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (2.81 g, 10.83 mmol) The reaction was stirred overnight, diluted with EtOAc (1500 mL), washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product (2.666 g, 9.65 mmol, 98% yield) as a light tan solid.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1.[C:16]([C:18]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:20][C:21](O)=[O:22])#[N:17]>O1CCCC1>[N:11]1([C:21](=[O:22])[CH2:20][CH2:19][C:18]([CH:24]([CH3:25])[CH3:26])([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:16]#[N:17])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: C1=CCNC1
Reactant: CC(C)C(C#N)(CCC(=O)O)c1cccs1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCC(=O)N1CC=CC1)c1cccs1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
Under nitrogen atmosphere, diethyl cyanophosphonate (618 mg) was added to a tetrahydrofuran solution (15 ml) of 3-pyrroline (262 mg) and 4-cyano-4-(2-thienyl)-5-methylhexanoic acid (692 mg) at room temperature, and the mixture was stirred overnight. After the reaction solution was evaporated, the crude product was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a yellow oil (440 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:3]=12.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:3]=12)[CH3:23]
Reactant: COc1ccc(Cn2ncc3c(Cl)c(C=O)cnc32)cc1
Reactant: CCN
Product: CCNc1c(C=O)cnc2c1cnn2Cc1ccc(OC)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1-(4-methoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (350 mg, 1.16 mmol), ethyl amine (70 wt. % solution in water, 2 mL, 25 mmol) is heated at 120° C. in a sealed tube. After overnight, the reaction mixture is cooled to room temperature and concentrated. The residue is dissolved in HCl solution (1N, 4 mL) and heated at 50° C. After stirring for 1.5 hours, the reaction mixture is basified with saturated sodium bicarbonate solution to pH=8. The solid is collected by filtration and washed with water, then hexanes, dried to afford the title compound as a solid. MS m/z 311.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1)(=O)[CH3:2].[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH:1]([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=2)[CH3:2])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CCN(C(C)c2ccnc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 50 °C

Procedure:
To a suspension of tert-butyl 4-acetylpyridin-2-ylcarbamate (16-3, 187 mg, 0.79 mmole) in MeOH (3 mL) was added 1-acetylpiperazine (304 mg, 2.37 mmole), glacial HOAc (0.14 mL, 2.3.7 mmole), and NaBH3CN (149 mg, 2.37 mmole) then the mixture was heated to 50° C. After 6 hr additional NaBH3CN (149 mg, 2.37 mmole) was added and heating continued. After 18 hr the mixture was cooled to RT, diluted with saturated NaHCO3, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-10% EtOH/EtOAc) gave the titled compound as an oil: 1H-NMR (500 MHz, CDCl3) δ8.17 (d, 1H, J=5.13 Hz), 7.87 (s, 1H), 7.52 (bs, 1H), 6.97 (d, 1H, J=5.13 Hz), 3.64-3.57 (m, 2H), 3.45-3.39 (m, 3H), 2.49-2.35 (m, 4H), 2.06 (s, 3H) 1.54 (s, 9H), 1.35 (d, 3H, J=6.59 Hz).