Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[O:11][N:10]=3)[CH2:8][CH2:7]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: c1cc2onc(N3CCNCC3)c2cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution in CH2Cl2 (10 ml) of 3-piperazin-1-yl-isoxazolo[4,5-c]pyridine dihydrochloride (840 mg, 3.0 mmol) and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (904 mg, 3.7 mmol; intermediate H; prepared according to WO2007/093540) was treated with Et3N (629 mg, 6.2 mmol) before addition of Na(AcO)3BH (1.03 g, 5 mmol). The reaction mixture was stirred 16 h at r.t., then sat. aq. NaHCO3 was added and the product was extracted with 2 portions of CH2Cl2. After drying (MgSO4) and evaporation of the solvent the product was purified by flash chromatography (50 g SiO2, EtOAc/MeOH 100:0→80:20) to obtain 930 mg (71%) of the title compound as an off white solid. m/z=430.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14]([OH:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.CN1C=CN=C1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:17][C@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of (3aR,4R,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-ol (3.2 g, 11.75 mmol) from Example 30 in dichloromethane (15 mL) was added triethylamine (4.10 mL, 29.4 mmol) followed by 1-methylimidazole (0.281 mL, 3.53 mmol). The solution was cooled to 0° C. and 4-bromobenzene-1-sulfonyl chloride (4.50 g, 17.63 mmol) was added. The solution was warmed to room temperature (solution turned cloudy) and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (12 mL) and washed with aqueous hydrogen chloride (0.1 N, 2×10 mL) and water (10 mL). The organic phase was dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography using 0-60% dichloromethane/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.99-7.90 (m, 2H), 7.77-7.67 (m, 2H), 7.51 (t, J=7.9, 1H), 6.99 (d, J=7.3, 1H), 6.45 (d, J=8.6, 1H), 5.17 (q, J=6.1, 1H), 3.69 (dd, J=11.4, 4.6, 1H), 3.57-3.47 (m, 1H), 3.37 (dd, J=11.4, 8.9, 1H), 3.23 (dd, J=10.7, 4.5, 1H), 2.90-2.78 (m, 1H), 2.67-2.54 (m, 1H), 2.02-1.88 (m, 1H), 1.80 (dq, J=8.2, 6.0, 1H), 1.70 (dtd, J=13.5, 8.6, 7.0, 1H), 1.51-1.37 (m, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:30][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:21])[N:7]2[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)[CH3:29]
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Reactant: CCN(CC)CCCCBr
Product: CCN(CC)CCCCn1c2cc(C)c(C)cc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(4-Diethylamino-n-butyl)-3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and 4-bromodiethylaminobutane.
Reaction SMILES: C(C[O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:23]([CH3:24])[CH2:22][CH2:21][C@:17]45[C:18]=2[C:19]=1[O:20][C@H:16]4[C@@H:15]([OH:25])[CH:14]=[CH:13][C@@H:12]35)(O)=O.ClC(OCC(C)C)=O>CN(C)C=O.O>[CH:8]1[C:9]2[CH2:10][C@H:11]3[N:23]([CH2:22][CH2:21][C@@:17]45[C@H:12]3[CH:13]=[CH:14][C@H:15]([OH:25])[C@@H:16]4[O:20][C:19]([C:18]=25)=[C:6]([OH:5])[CH:7]=1)[CH3:24]
Reactant: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Carboxymethyl morphine (240 mg) suspended in 8 ml dry dimethyl formamide (DMF) was cooled to -15° C. and treated with 84 μl isobutyl chloroformate. The solid dissolved while stirring for 30 minutes at -15° C. Bovine serum albumin (BSA) (400 mg) dissolved in 56 ml water containing 2.6 g sodium bicarbonate was added to this solution and the mixture was kept at 0° C. overnight. It was then dialyzed against distilled water with four changes of water (dialysis 1:80) and lyophilized to give 350 mg of conjugate.
Reaction SMILES: [C:1]([C:3]([CH2:15][CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](OCC)=[O:5])#[N:2].[NH3:17]>C(O)C>[C:1]([C:3]([CH2:15][CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([NH2:17])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)(CC)c1ccccc1
Reactant: N
Solvent: CCO
Product: CCC(C#N)(C(N)=O)c1ccccc1
Reaction time: 96 h
Yield: 80 %

Procedure:
A 10% solution of ethyl 2-cyano-2-ethyl-2-phenylacetate in ethanol is saturated with ammonia under cooling. The reaction mixture is allowed to stand at 5° C. for 96 hours, thereafter the solvent and the excess of ammonia are removed, and the product is filtered off. 2-Cyano-2-ethyl-2-phenylacetic acid amide is obtained with a yield of 80%; m.p.: 116.5°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.OCC([C:28]1[C:33]([N+:34]([O-])=O)=[C:32]([CH3:37])[CH:31]=[CH:30][C:29]=1[S:38]([NH2:41])(=[O:40])=[O:39])(C)C>>[OH:22][CH2:20][C:19]([NH:41][S:38]([C:29]1[CH:30]=[CH:31][C:32]([CH3:37])=[C:33]([NH:34][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:15][CH2:16]4)=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:22])[CH:28]=1)(=[O:39])=[O:40])([CH3:18])[CH3:10]
Reactant: Cc1ccc(S(N)(=O)=O)c(C(C)(C)CO)c1[N+](=O)[O-]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B.11) according to general procedure II. Pale-yellow solid. MS (ISP) 554.3 [(M+H)+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C(OCC)C>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: CNc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(c1ccccc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Step 1—To a stirring solution of N-methylaniline (80 g, 0.75 mol) in diethyl ether (600 ml) cooled at −78° C. was added n-butyl lithium (2.4 M in hexanes, 342 ml, 0.82 mol) keeping the temperature below −60° C. The resulting slurry was stirred for 1 hour then chlorotrimethylsilane (114 ml, 0.90 mol) was added while keeping the temperature below −70° C. The reaction was allowed to warm to room temperature overnight then filtered to remove the precipitated white solid. The filtrates were concentrated in vacuo then distilled under high-vac to yield the N-trimethylsilyl-N-methylaniline (126 g, 94%) as a colorless/straw colored liquid: b.p. 48° C./0.6 mmHg; 1H NMR (CDCl3) 0.33 (s, 9H), 2.95 (s, 3H), 6.85 (t, 1H, 7 Hz), 6.94 (d, 2H, 8 Hz), 7.27 (t, 2H, 9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:12]2[NH:11][N:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])=[CH:7][CH:6]=3)[C:13]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Nc3n[nH]c(NCc4ccc(O)cc4)c3C(N)=O)cc2)cc1
Reaction time: 0.25 h
Yield: 12 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in 25.00 mL of DMF along with TEA (211 μL, 2.50 eq.) and stirred on ice for 15 minutes. p-Toluenesulfonyl chloride (145 mg, 1.25 eq.) dissolved in 1 mL of DMF was slowly dripped into to the reaction vessel and continued to stir for 18 hrs allowing the reaction to reach room temperature. Once the reaction was complete, traces of starting material is no longer present and confirmed by HPLC, water was added to the reaction until a white precipitate formed. The white precipitate was then collected via filtration and dried under vacuum for 18 hrs (30 mg, 12% yield).
Reaction SMILES: [Br:1]C1C=C2C(C=CN2)=CC=1F.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:24])[CH:22]=2)[N:17]([CH2:26][C:27]([OH:29])=[O:28])[CH:16]=1)(=[O:14])[NH2:13]>>[Br:1][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([C:12](=[O:14])[NH2:13])=[CH:16][N:17]2[CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=1[F:24]
Reactant: NC(=O)c1cn(CC(=O)O)c2cc(F)c(F)cc12
Reactant: Fc1cc2cc[nH]c2cc1Br
Product: NC(=O)c1cn(CC(=O)O)c2cc(Br)c(F)cc12

Procedure:
was prepared from 6-bromo-5-fluoro-1H-indole [259860-08-7] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 315.0 [M+H]+, 631.0 [2M+H]+; tR (HPLC conditions k): 2.79 min.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[N:22]=[CH:21][CH:20]=[C:19]([F:23])[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:20]1[CH:21]=[N:22][C:10]([F:9])=[C:11]([C:19]=1[F:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)c1c(F)ccnc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)ncc(Cl)c1F
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
Into a solution of LDA in THF (20 mL, 12 mmol) was added a solution of tert-butyl 2,4-difluoronicotinate (2.14 g, 10 mmol) in THF (12 mL) at −78° C. The mixture was stirred for 30 min and then a solution of hexachloroethane (2.96 g, 12.5 mmol) in THF (7.0 mL) was added. The temperature was allowed to rise to 0° C. The reaction was then quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate and the organic layers were combined, dried over sodium sulfate, evaporated and purified by silica chromatography (0-8% ethyl acetate in hexanes) to give tert-butyl 5-chloro-2,4-difluoronicotinate (1.2 g, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:21]([CH3:25])[C:22](=O)[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:21]([CH3:25])[CH:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CC(=O)C(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1[nH]c2ccc(OC(C)C(C)N3CCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
2-Methyl-5-(1-methyl-2-oxo-propoxy)-1H-indole-3-carboxylic acid benzyl ester (0.248 g, 0.707 mmol) and pyrrolidine (0.05 g, 0.706 mmol) were mixed together in dichloroethane and stirred under N2 at room temperature for 1 hour. The reaction was then cooled to 0° C. whereupon sodium triacetoxyborohydride (0.209 g, 0.988 mmol) was added. After 30 minutes, the reaction was then permitted to warm to rt and stirred for a further 2 hours. It was then stopped by the addition of 1N NaOH (10 mL). The mixture was then extracted with EtOAc and the combined organic layers washed with brine and dried over anhydrous Na2SO4 Purification on SiO2 (10% MeOH/CH2Cl2) gave 0.110 g (38%) of the desired compound, mp 94-98° C. 1HNMR (400 MHz, DMSO): 1.58 (d, J=6.10 Hz, 3H), 1.60 (b, 4H), 2.40 (b, 4H), 2.59 (s, 3H, ArCH3),3.35 (b, 1H), 4.43 (m, 1H), 5.26 (s, 2H), 6.69 (d, J=8.44 Hz, 1H), 7.19 (d, J=8.64 Hz, 1H), 7.28-7.44 (m, 6H), 11.72 (s, H, H). MS APCI+) m/z 407.2(MH+). Anal. Calcd for C25H30N2O3.0.20H2O: C, 3.21;H,7.47; N, 6.83. Found: C, 72.84: H, 7.57: N, 6.56 I (KBr): 3294, 2973, 1691, 1665, 1454, 1167, 1073 cm−1.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])(C)C>>[C:8]([C:4]1[CH:3]=[C:2]([C:15]#[C:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Reactant: CC(=O)c1cccc(I)c1
Product: CC(=O)c1cccc(C#Cc2cncc(C#N)c2)c1
Yield: 48.7 %

Procedure:
Prepare according to the general procedure outlined in EXAMPLE 72 using 3′-iodoacetophenone (1.29 g, 5.24 mmol) and 5-trimethylsilanylethynyl-nicotinonitrile (1.0 g, 5.0 mmol), (prepared as described in PREPARATION 3), to give the title compound (600 mg, 49%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(=O)O[CH2:13][CH2:12][O:11]1>[Br-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[OH:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1OCCO1
Reactant: O=Cc1ccccc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1OCCO
Temperature: 140 °C

Procedure:
A mixture of 0.2 mol of 2-hydroxybenzaldehyde, 0.2 mol of ethylene carbonate and 0.3 mol of tetraethylammonium bromide was heated at 140° C. for 2 hours. After cooling, the reaction mixture was taken up in ethyl acetate, washed with water, dried over MgSO4 and evaporated. The compound was purified by distillation.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:25])=[C:5]2[C:20]([C:21]([NH:23][NH2:24])=[O:22])=[N:19][NH:18][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[F:17])#[N:2].[CH2:26]([N:28]([CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][N:32]=[C:33]=S)[CH3:27].Cl.C(N=C=NCCCN(C)C)C.O>CC(N(C)C)=O>[CH2:26]([N:28]([CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][NH:32][C:33]1[O:22][C:21]([C:20]2[C:5]3[C:6](=[N:7][C:8]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=4[F:17])=[C:3]([C:1]#[N:2])[C:4]=3[CH3:25])[NH:18][N:19]=2)=[N:23][N:24]=1)[CH3:27]
Reactant: CCN(CC)CCCN=C=S
Reactant: COc1ccc(-c2nc3[nH]nc(C(=O)NN)c3c(C)c2C#N)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CC)CCCNc1nnc(-c2n[nH]c3nc(-c4ccc(OC)cc4F)c(C#N)c(C)c23)o1
Temperature: 65 °C
Yield: 60.6 %

Procedure:
To 200 mg (0.59 mmol) of 5-cyano-6-(2-fluoro-4-methoxyphenyl)-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-carbohydrazide diluted in 8 ml of dimethylacetamide, are added 101 mg of N,N-diethyl-3-isothiocyanatopropane-1-amine. The reaction mixture is stirred at 65° C. until complete disappearance of the starting product. 224 mg (1.17 mmol) of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride are added and the solution is stirred at 70° C. for 2 h. 20 ml of water are added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The solid is triturated in a diethyl ether/methanol mixture (10:1) to yield 170 mg of 3-(5-(3-(diethylamino)propylamino)-1,3,4-oxadiazol-2-yl)-6-(2-fluoro-4-methoxyphenyl)-4-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH2:21][CH2:22][N:23]([C:25]1[CH:32]=[CH:31][C:28](C=O)=[CH:27][CH:26]=1)[CH3:24]>>[OH:20][CH2:21][CH2:22][N:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCO)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CN(CCO)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A one liter three (3) necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid, and piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, a 33.62 g quantity of 4-[N-(2-hydroxyethyl)-N-methylamino]benzaldehyde is added.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][O:28][CH2:29][C:30]1[NH:31][C:32]([NH:35][CH:36]([CH3:39])[CH2:37][CH3:38])=[N:33][N:34]=1>>[CH3:27][O:28][CH2:29][C:30]1[N:31]=[C:32]2[N:35]([CH:36]([CH3:39])[CH2:37][CH3:38])[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:33]2[N:34]=1
Reactant: CCC(C)Nc1nnc(COC)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)CC)c2nc(COC)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.75 g) and 5-(methoxymethyl)-N-(1-methylpropyl)-4H-1,2,4-triazol-3-amine (0.2 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 41%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[N:25]=[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:25]=[C:13]2[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccn2nc(C)nc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccn2nc(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (0.830 g, 20.8 mmol) in dimethyl sulfoxide (10 mL) was added a solution of trimethylsulfoxonium iodide (4.57 g, 20.8 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-8-yl)acrylate (4.00 g, 17.3 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (1.84 g, yield 43%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 74.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.126 g, 0.274 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with triethylamine (0.0760 mL, 0.548 mmol) and 2-chlorobenzenesulfonyl chloride (0.0867 g, 0.411 mmol) to obtain 4-(2-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.130 g, yield 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([Br:10])=[CH:8][N:9]=1)[C:5]#[N:6].C([O-])(O)=O.[Na+].Cl[CH2:17][CH:18]=O>CCO>[Br:10][C:7]1[C:4]([C:5]#[N:6])=[CH:3][C:2]2[N:9]([CH:17]=[CH:18][N:1]=2)[CH:8]=1
Reactant: N#Cc1cc(N)ncc1Br
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc2nccn2cc1Br
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinonitrile (5.0 g, 25.3 mmol), NaHCO3 (3.6 g, 42.9 mmol) and chloracetaldehyde (17.0 mL, 114.0 mmol) in EtOH (160 mL) was vigorously stirred and refluxed for 14 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was suspended in DCM (500 mL) and brine (100 mL). The aqueous layer was separated and extracted with DCM (5×), and the combined organic fractions were dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (2.97 g, 13.4 mmol, 53%) as an orange solid. MS: 223 [M+1]+; HPLC: AtRet=0.54; TLC: RF 0.17 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[C:16]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>ClCCl>[NH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:29]=[CH:30][C:14]([NH:13][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:15][C:16]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: COc1ccc(C(=O)O)c(F)c1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(OCCN)c(-c3c(Cl)cnn3C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-4-methoxybenzoic acid (92.8 mg, 545 μmol), tert-butyl 2-(4-amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (200 mg, 545 μmol), HATU (207 mg, 545 μmol) and triethylamine (76.0 μL, 545 μmol) in dichloromethane was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. To the crude product was added 2M HCl (5 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated and the title compound was obtained as a yellow oil. LCMS m/z (%)=419 (M+H, 35Cl, 100), 421 (M+H, 37Cl, 40).