Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([Si](C)(C)[O:33][CH2:34][CH:35]=O)(C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:35][CH2:34][OH:33])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (tertbutyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off in THF using 5 equivalent of a 1M TBAF/THF solution: The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness. The product was purified by means of reversed-phase chromatography. The fractions were extracted under basic conditions, dried, filtered and evaporated.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[Cl:20])(=[O:3])[CH3:2]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 55 °C
Yield: 84.5 %

Procedure:
A mixture of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (8.7 g, 0.037 mol), thionyl chloride (120 ml, 1.65 mol) and DMF (1 ml) was stirred and heated to 55° C. for 6 hours. The mixture was cooled to room temperature and thionyl chloride was evaporated. The solid was dissolved in chloroform and the solution was washed with sodium bicarbonate and brine, the chloroform was evaporated under reduced pressure to give 7.9 g of a gray product. MS (ESI) m/z: 253 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:17]([CH2:18][CH2:19][OH:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.CN(C)C=O.[H-].[Na+].Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:17]([CH2:18][CH2:19][O:20][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: Clc1ncccn1
Reactant: CN1CCC(Nc2nc3cccnc3n2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Nc2nc3cccnc3n2CCOc2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred mixture of 4.13 parts of 2-[(1-methyl-4-piperidinyl)amino]-3H-imidazo[4,5-b]pyridine-3-ethanol and 90 parts of N,N-dimethylformamide were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at room temperature, 1.7 parts of 2-chloropyrimidine were added. The whole was stirred for 1 hour at room temperature and the reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.7 parts (32.0%) of N-(1-methyl-4-piperdinyl)-3-[2-(2-pyrimidinyloxy)ethyl]-3H-imidazo[4,5-b]-pyridin-2-amine; mp. 158.1° C. (compound 168).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH3:28][C:29]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:32]([O:5][CH2:4][C@@H:3]([NH2:2])[CH2:6][NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]3)[CH2:16]1)[CH2:10]2)([C:29]([CH3:31])([CH3:30])[CH3:28])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N[C@H](CO)CNCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC[C@@H](N)CNCC12CC3CC(CC(C3)C1)C2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a solution of (S)-2-amino-3-((1-adamantylmethyl)amino)propan-1-ol HCl salt (1.2 g, 3.8 mmol) in anhydrous CH2Cl2 (20 mL) were added DIEA (1.9 g, 15.2 mmol), DMAP (2.3 mg, 0.02 mmol) and TBDPSCl (1.2 g, 4.2 mmol) at 0° C. The mixture was stirred at rt for 2 h. The reaction solution was extracted with CH2Cl2 (100 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, and concentrated to give the crude product, which was purified by preparative TLC (PE:EtOAc 10/1) to afford (S)-3-(tert-butyldiphenylsilyloxy)-N1-(1-adamantylmethyl)propane-1,2-diamine (620 mg, 29%) 1H NMR: (CDCl3, 400 MHz): δ=1.05 (s, 9H), 1.54 (s, 6H), 1.62-1.73 (m, 6H), 1.98 (s, 3H), 2.32 (d, 1H), 2.45 (d, 1H), 2.56 (d, 1H), 2.85 (d, 1H), 3.15 (m, 4H), 3.65 (m, 2H), 7.4 (m, 6H), 7.62 (m, 4H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 50% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-11.62 (c=0.45, methanol).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH2:14]([O:21][C:22]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Reaction time: 5 h

Procedure:
To a stirred solution of 3-hydroxymethylpiperidine (5 g, 43.4 mmol, 1 eq) in CHCl3 (150 mL) was added saturated aqueous NaHCO3 (150 mL). To the vigorously stirred mixture was added benzyl-chloroformate (6.8 mnL, 47.74 mmol, 1.1 eq) via syringe. The mixture was stirred 5 h. The layers were separated and the aqueous layer was extracted 2× with CH2Cl2. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The material was used crude.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: C1CCNC1
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Agent: [I-]
Agent: [K+]
Product: Ic1ccc(-c2nnc(CN3CCCC3)o2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in pyrrolidine (2 ml) and stirred for 18 hours at 20° C. The amine was then removed in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[S:11][CH:12]=[CH:13][C:9]=3[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][C:6]2=[O:20])[CH2:3][CH2:2]1.C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29].N>>[CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([N+:28]([O-:30])=[O:29])=[CH:13][C:9]=3[C:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:7][C:6]2=[O:20])[CH2:2][CH2:3]1
Reactant: O=c1nc(-c2ccccc2)c2ccsc2n1CC1CC1
Reactant: O=[N+]([O-])O
Agent: N
Solvent: CC(=O)OC(C)=O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])sc2n1CC1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 380 mg of 1-cyclopropylmethyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one and 1.2 ml of acetic anhydride is added 380 mg of fuming nitric acid (d = 1.50) is 1.20 ml of acetic anhydride. The reaction mixture is stirred for 48 hours at room temperature, then neutralized with aqueous ammonia under ice-cooling and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and evaporated under reduced pressure to give crystals, which are recrystallized from chloroform-ethanol to give 1-cyclopropylmethyl-4-phenyl-6-nitro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 216° - 218°C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[O:14][C:15]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3c(C)cccc3C)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1cccc(C)c1-c1cccc2c1CC(CN=[N+]=[N-])O2
Yield: 90.9 %

Procedure:
Treatment of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.27 g, 5.55 mmol) with sodium azide (1.44 g, 22.23 mmol) generally according to the procedure described for Intermediate 98 gave 1.41 g (91%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.141 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.36 g (93%) of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 254-256° C.; Anal. calcd. for C17H19NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.03; H, 7.05; N, 4.66.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](B2OC(C)(C)C(C)(C)O2)=[C:8]([NH:10]C(=O)OC(C)(C)C)[CH:9]=1)([O-:3])=[O:2].Br[C:28]1[C:29]([C:34]#[N:35])=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2=[C:28]3[C:29](=[C:34]([NH2:35])[N:10]=[C:8]2[CH:9]=1)[N:30]=[CH:31][CH:32]=[CH:33]3)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from the previous step) (1.0 eq.) and 3-bromopicolinonitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction mixture was filtered to collect the precipitate. The precipitate was rinsed with EtOAc to give 8-nitrobenzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: CS(O[C@H:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][C:8]([NH2:10])=[O:9])(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@@H:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][C:8]([NH2:10])=[O:9])=[N+:25]=[N-:26]
Reactant: CCCCCCCCCCCCC[C@H](CC(N)=O)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)N=[N+]=[N-]
Yield: 51.6 %

Procedure:
A solution of (R)-3-methanesulfonyloxyhexadecanamide (32 mg) and sodium azide (12 mg) in N,N-dimethylformamide (1 ml) was heated at 60° C. for 2 hours. The cooled mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with water (10 ml), and brine (10 ml), dried, and concentrated under vacuum, then the residue was recrystallized at -20° C. from a mixture of ethyl acetate (0.2 ml) and n-hexane (2 ml) to give (S)-3-azidohexadecanamide (14 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][N:15]1[CH2:16][CH2:17][CH:12]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH2:13][CH2:14]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Nc1ncnc2c1c(I)nn2C1CCN(Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.45 mmol), 1H-2-imidazolecarbaldehyde (0.42 g, 4.34 mmol), sodium triacetoxyborohydride (0.61 g, 2.90 mmol) and glacial acetic acid (0.26 g, 4.36 mmol) were mixed with 1,2-dichloroethane (20 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.57 g, 92%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.17 (m, 4H), 2.92 (m, 2H), 3.55 (s, 2H), 4.57 (m, 1H), 6.92 (s, 2H), 8.14 (s, 1H).
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:32]=[CH:31][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].C([O-])(O)=O.[Na+].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39]([NH:7][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:31][CH:32]=1)=[NH:6])=[O:40])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of 9C (570 mg, 1.12 mmol) in CH2Cl2 (12 mL) was added 1.0 M NaHCO3 (11.2 mL, 11.2 mmol), followed by benzyl chloroformate (0.22 mL, 1.5 mmol) in CH2Cl2 (3.0 mL). The mixture was stirred at rt for 30 min. TLC indicated some 9C still present. Another portion of benzyl chloroformate (0.1 mL, 0.84 mmol) in CH2Cl2 (3.0 mL) was added. After stirring at rt for 1.0 h, the reaction was quenched with ammonium hydroxide (0.65 mL), and extracted with CH2Cl2. The organic extract was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (1:1) to give 9D (570 mg, 73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (d, J=6.16 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H) 3.71 (s, 3H) 4.04 (q, J=7.03 Hz, 2H) 4.46 (m, 1H) 5.18 (s, 2H) 5.58 (s, 1H) 6.85 (d, J=8.8 Hz, 1H) 6.90 (d, J=8.35 Hz, 2H) 7.09 (m, 2H) 7.20-7.40 (m, 6H), 7.82 (d, J=9.20 Hz, 2H).
Reaction SMILES: [H-].[Na+].CCO.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[C:20]([CH2:26]Br)[CH:19]=1>CCOCC>[Br:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[CH2:24][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccc(Br)cc2C1
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
Sodium hydride (60% in mineral oil, 123 mg, 3.1 mmol) was added in small portions to EtOH (2 mL) in Et2O (6 mL) at room temperature under N2. After the addition was complete, the nearly clear and colorless solution was stirred for 5 min. To this solution, diethyl malonate (234 mg, 1.46 mmol) was added followed by the addition of 4-bromo-1,2-bis(bromomethyl)benzene (500 mg, 1.46 mmol). Immediately, a precipitate was formed, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified on silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound (360 mg, 72%). 1HNMR (400 MHz, DMSO-d6): δ 7.44 (d, 1H), 7.35 (d, 1H), 7.20-7.18 (m, 1H), 4.15 (q, 4H), 3.48 (s, 2H), 3.43 (s, 2H), 1.16 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:20])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1cccc(Nc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of N-(3-aminophenyl)-2-(3-nitrophenyl)acetamide-hydrogen chloride (0.11 g, 0.35 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was then added an stirred overnight again. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The resulted mixture was purified by column chromatography to give the desired product (0.080 g, 53%). LCMS for C18H13Cl2N5O3 (M+H)+: m/z=418.0, 419.9. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 9.53 (s, 1H), 8.35 (s, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.12 (ddd, J=8.2, 2.4, 1.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 7.78 (dt, J=7.8, 1.4 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.36 (dt, J=8.0, 1.7 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.25 (dt, J=8.0, 1.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=O.[NH2:19][C:20]1[C:21]([CH3:29])=[N:22][N:23]([CH2:26][CH:27]=[CH2:28])[C:24]=1Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[N:1]=[C:24]2[N:23]([CH2:26][CH:27]=[CH2:28])[NH:22][C:21]([CH3:29])=[C:20]2[N:19]=1
Reactant: C=CCn1nc(C)c(N)c1Cl
Reactant: Cc1cc(N)c(C(=O)c2ccccc2Cl)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(C)c(C)cc3N=C21
Temperature: 170 °C

Procedure:
A mixture of 3.0 g (0.0116 mole) of (2-amino-4,5-dimethylphenyl)-(2-chlorophenyl)-methanone (Xw), 2.0 g (0.0116 mole) of 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), 2.21 g (0.0116 mole) of p-toluenesulfonic acid monohydrate and 40 mL of isopropanol was heated in a sealed tube at 170° C. for 90 minutes. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and then washed twice with saturated sodium bicarbonate solution. The aqueous washes were reextracted with ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Trituration of the residue with hexane gave the intermediate 5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVw), as a yellow solid. Purification of the filtrates by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:1) provided additional XIVw and was combined with the material obtained above for a total yield of 2.7 g of XIVw as a yellow solid, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7](N3CCNCC3)=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][C@H:25]1[CH2:26][OH:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:27][CH2:26][CH:25]3[CH2:28][CH2:29][CH2:30][N:24]3[CH3:23])=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:20]([NH2:22])=[O:21]
Reactant: CN1CCC[C@H]1CO
Reactant: CCCc1cc(N2CCNCC2)nc2sc(C(N)=O)c(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cc(OCC2CCCN2C)nc2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixture pyridine-triflate intermediate (see Example 1) (10 mg) and N-methyl-L-prolinol (40 mg) in dioxane was heated under Ar at 90° C. for 3 h. The mixture was cooled to room temperature, and Na2CO3 (2 M, 0.2 mL) was added. The mixture was heated at 100° C. under Ar for 10 h, cooled to room temperature and diluted with water (1 mL). The mixture was extracted with EtOAc, dried with Na2SO4 and concentrated. The residue was purified by preparative silica gel chromatography to give 6 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][CH3:27])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>N1C=CC=CC=1>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:13][CH:14]=2)[N:9]([CH2:26][CH3:27])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])=[CH:3][CH:4]=1)#[N:18]
Reactant: CCC(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(N3CCN(C)CC3)cc21
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(-c2c(C#N)c3ccc(N4CCN(C)CC4)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of the compound obtained in step B (54 mg, 0.15 mmol) in dry pyridine (1.5 mL) is added propionyl chloride (26 μL, 0.30 mmol). The mixture is stirred at room temperature overnight and the solvent is removed in vacuo. The residue is dissolved with DCM (5 mL) and washed with water (2×4 mL) and chromatographed (silica gel, MeOH/DCM, 0.5/9.5) to provide product, {N-{4-[3-cyano-1-ethyl-6-(4-methylpiperazin-1-yl)indol-2-yl]phenyl}propionamide (45 mg, 73%).