Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][CH2:12][O:13][CH3:14])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH2:19].[S-2].[Na+].[Na+].Cl.C[OH:26]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10](=[O:26])[CH2:11][CH2:12][O:13][CH3:14])[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: CO
Reactant: COCC#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Product: COCCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 75 °C
Yield: 13 %

Procedure:
To a solution of 2-amino-5-(3-methoxy-prop-1-ynyl)-4-trifluoromethyl-benzoic acid methyl ester (1.19 g, 4.15 mmol) in MeOH (100 mL) were added successively a solution of sodium sulfide (0.1 M, 12.4 mL, 1.24 mmol), followed by 10% aq HCl-solution (3.70 mL, 12.45 mmol). The reaction mixture was heated to 75° C. for 29 h, cooled and filtered over Celite. Evaporation of the filtrate gave a yellow oil which was purified by MPLC (oRP-C18 column (particle size 5-21 μM) with 1:1 CH3CN/water. The fractions containing the product were combined, the acetonitrile was distilled off and the residual water phase was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4) and the solvent was removed in vacuo to provide the title compound (0.167 g, 13%) as a white powder, mp 89-91° C. IR (FTIR microscope in transmission): 1696 m, 1674 s cm−1.
Reaction SMILES: C(OC(=O)[N:7]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)[CH2:8][C:9]1[N:10]=[C:11]([CH2:22][OH:23])[N:12](COCC[Si](C)(C)C)[CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])O.[Na+]>O>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:7][CH2:8][C:9]2[N:10]=[C:11]([CH2:22][OH:23])[NH:12][CH:13]=2)[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(CO)n1)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OCc1nc(CNC2CCN(Cc3ccccc3)CC2)c[nH]1
Temperature: 25 °C
Yield: 103.1 %

Procedure:
tert-Butyl(1-benzyl-4-piperidinyl)((2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (0.48 g) obtained in Example 83e) was dissolved in a mixed solution (TFA:water=1:1, 2 ml), and mixed at 80° C. for 3 hours. After cooling to room temperature, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a yellow oil (0.28 g, quantitative).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[I-:14].[Na+].O>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:8][I:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)ccc1F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(CI)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 3-tert-butyl-4-fluorobenzyl bromide (1.49 g, 6.08 mmol) in acetone (50 ml), sodium iodide (9.1 g, 60.8 mmol) was added, followed by stirring at room temperature overnight. The reaction mixture was mixed with water and extracted with n-hexane. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane) to give the titled compound (1.18 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([OH:17])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:20])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([Cl:20])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
The title compound was prepared by stirring a mixture of 5-(4-nitrophenyl)-2-furoic acid (1.0 g; 4.3 mmol) and thionyl chloride (10 ml) at reflux for 2 hours. The mixture was evaporated and co-evaporated with anhydrous toluene. The acid chloride was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][SH:8])[C:4](Br)=[CH:3][CH:2]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+].S(=O)(=O)(O)O.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCCC1.CCCCCC>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=3[CH2:7][S:8]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: SCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Reaction time: 1.5 h
Yield: 45.8 %

Procedure:
In 800 ml of tetrahydrofuran, 81.0 g (0.40 mole) of 2-bromobenzylthiol were dissolved, followed by the dropwise addition of 516 ml (0.84 mole) of n-butyl lithium (1.6 mole, a hexane solution) at −78° C. over 6 hours. After stirring at the same temperature for 1.5 hours, a solution of 79.5 g (0.40 mole) of N-tert-butoxycarbonyl-4-piperidone in 800 ml of tetrahydrofuran was added dropwise to the reaction mixture over 3 hours and then the mixture was stirred for a further 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to afford a residue. To the residue, 2 liters of 4N sulfuric acid were added and the mixture was heated under reflux for 14 hours. Under ice-cooling, the reaction mixture was made alkaline with 350 g (8.75 mole) of sodium hydroxide, followed by addition of 102 g (0.47 mole) of di-tert-butyl dicarbonate. The resulting mixture was stirred for 1 hour. The reaction mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent of the extract under reduced pressure was purified by chromatography on a silica gel column (eluting solvent; n-hexane:ethyl acetate=97:3), whereby 56 g of the title compound were obtained as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[C:26]1NN=[N:28][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=2[Cl:18])=[N:27][N:28]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(-c2nnn[nH]2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2cccc(Cl)c2Cl)o1
Yield: 36.6 %

Procedure:
The title compound (0.70 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.13 g), 5-(2,3-dichlorophenyl)tetrazole (1.0 g) and dicyclohexylcarbodiimide (0.98 g) according to the method of description 1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20]C)=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.CC(OC1NC(N)=C2C(N=1)=NC(OC)=N2)C.BrCCCC[CH2:51][Cl:52]>>[Cl:52][CH2:51][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]([CH3:20])[CH3:22])=[N:10][C:11]=2[NH2:17]
Reactant: ClCCCCCBr
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-5-chloropentane.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C([Li])CCC.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:22]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: CCCCCI
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (1.0 g, 4.93 mmole) in 12 mL tetrahydrofuran (THF) was cooled to −78° C. and treated dropwise with 2.5 M n-butyllithium solution (2.2 mL) and allowed to warm to −20° C. over a one hour period. Iodopentane (1.28 mL) was introduced at −20° C., the mixture stirred at room temperature for three hours, poured into 50 mL of a saturated aqueous sodium bicarbonate solution and extracted with three portions of 50 mL of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) providing 1.1 g (82%) of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (51) as a colorless oil.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:41])[CH2:31][N:32]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[N:33]3)[CH:26]=[N:27][CH:28]=2)=[O:22])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1>[F:20][C:18]1[C:19]2[N:11]([C:8]([CH3:9])([CH3:10])[CH2:7][OH:6])[CH:12]=[C:13]([C:21]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:41])[CH2:31][N:32]4[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[N:33]4)[CH:26]=[N:27][CH:28]=3)=[O:22])[C:14]=2[CH:15]=[N:16][CH:17]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(4-trifluoromethyl-pyrazol-1-yl)-acetamide (Preparation 4, 35 mg, 56 μmol) in THF (2 mL) 4M dioxane-HCl (0.5 mL) was added and stirred at room temperature for 18 hours. The reaction was evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid in 100% yield, 28.54 mg.
Reaction SMILES: [CH2:1]([C@H:8]([C@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Rh]>[CH:2]1([CH2:1][C@H:8]([C@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCC[C@@H](O)[C@@H](Cc1ccccc1)C(=O)OC
Agent: [Rh]
Solvent: CO
Product: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)OC
Yield: 100 %

Procedure:
Methyl (2R,3R)-2-benzyl-3-hydroxyhexanoate (3.35 g, 14.2 mmol) is dissolved in 35 mL of MeOH. Under an argon atmosphere 1.00 g of 5% rhodium on carbon is added. The reaction vessel is evacuated and refilled with hydrogen several times and then pressurized with hydrogen to 65 psi. After 8 h the reaction vessel is evacuated and refilled with nitrogen. The solution is filtered and the filtrate concentrated in vacuo giving methyl (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoate as an oil (3.44 g, 99% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([N+:16]([O-:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2>C1(C)C=CC=CC=1>[N:5]([C:6]12[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][C:8]([N+:16]([O-:18])=[O:17])([CH2:14]3)[CH2:7]1)[CH2:15]2)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: NC12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Solvent: Cc1ccccc1
Product: O=C=NC12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reaction time: 6 h
Yield: 90 %

Procedure:
10 mmole of 1-amino-3-nitroadamantane obtained by the method of Example 66 was dissolved in toluene (100 ml). To the resultant solution, 12 mmole of phosgene was added at the room temperature and stirred for 6 hours. As a result, The conversion of 1-amino-3-nitroadamantane was 99%, and 1-isocyanato-3-nitroadamantane (yield 90%) was formed.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:15]1([C:25]2[C:34]3[N:33]=[CH:32][CH:31]=[N:30][C:29]=3[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C1(B(O)O)C2C(=CC=CC=2)C=CC=1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:35]([C:28]3[C:29]4[N:30]=[CH:31][CH:32]=[N:33][C:34]=4[C:25]([C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=[CH:17][CH:16]=4)=[CH:26][CH:27]=3)=[O:36])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(-c2cccc3ccccc23)c2nccnc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: OB(O)c1cccc2ccccc12
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in in Step 14.1 but stirring the reaction mixture overnight and using 4-(4-methylpiperazin-1-yl)-aniline (WO2006000420) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid. The latter compound was synthesized as described in Steps 1.2-1.7 but using 1-naphtylboronic acid in Step 1.4. Title compound: ESI-MS: 474.0 [M+H]+; tR=4.34 min (System 1); TLC: Rf=0.45 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:27]1([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]5[CH:17]=[N:18][C:19]([N:22]6[CH2:26][CH2:25][CH2:24][CH2:23]6)=[N:20][CH:21]=5)=[O:15])=[CH:5][C:4]=4[N:1]=3)=[CH:42][CH:43]=2)=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cnc(N2CCCC2)nc1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4cnc(N5CCCC5)nc4)ccc3[nH]2)cc1

Procedure:
Compound 221 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C29H25N7O2: 504.22; found: 503.92.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[CH2:28][O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:45](Br)[C:46]#[CH:47]>CCOCC>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]2[C:15]([C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[CH2:28][O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[N:9]2[CH2:47][C:46]#[CH:45])=[CH:14][CH:13]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Reactant: C#CCBr
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To an ice cooled solution of methyl-3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl) oxy]methyl}phenyl)-1H-indole-6-carboxylate (Example 12, Step 4) in DMF (0.13 M) 60% NaH (2 eq.) was added. After 20 min. propargyl bromide (solution 80% in toluene) (1.5 eq.) was added and the mixture stirred at 0° C. for 1 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents the product was obtained as a white solid (96%). MS (ES+): 588.7 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].O.[NH2:13][NH2:14]>C1COCC1>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.01 M 2,6-difluoronitrobenzene and 0.01 M hydrazine hydrate (99% strength) in 30 ml of THF was stirred overnight at RT (exothermic reaction) and the residue was brought to crystallization after distilling off the solvent by treating with diisopropyl ether. Crystalline substance, m.p.: 93-95° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]4[S:21][C:20]([CH3:22])=[N:19][C:18]=4[CH:23]=3)=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH2:24].F[C:26]1[C:31]([C:32]2[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[CH:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]4[S:21][C:20]([CH3:22])=[N:19][C:18]=4[CH:23]=3)=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH:24][C:26]1[C:31]([C:32]2[CH:33]=[C:34]([NH:38][CH3:39])[N:35]=[CH:36][N:37]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CNc1cc(-c2cccnc2F)ncn1
Reactant: Cc1nc2cc(Nc3nccc4c(N)c(C)ccc34)ccc2s1
Agent: Cl
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Nc4ccc5sc(C)nc5c4)nccc23)ncn1
Temperature: 87 °C

Procedure:
6-methyl-N1-(2-methylbenzo[d]thiazol-5-yl)isoquinoline-1,5-diamine hydrochloride (5.94 g, 16.6 mmol) and 6-(2-fluoropyridin-3-yl)-N-methylpyrimidin-4-amine (4.74 g, 23.2 mmol, 1.40 equiv.) were combined in a 350 mL screw-cap pressure tube and flushed with nitrogen. 1M LiHMDS in THF (102 mL) were added in two portions (2×51 mL) at room temperature. The pressure tube was sealed and placed immediately in a pre-heated (87° C.) sonicator bath. The reaction mixture was sonicated at 85° C. for 30 min., cooled to room temperature. The resulting thick suspension was diluted with THF (0.2 L) and quenched into a mixture of sat. aq. NH4Cl (50 mL) and brine (100 mL). The organic layer was separated and concentrated in vacuo with silica (26 g). Column chromatography (CH2Cl2:THF 3:1)—two fractions were collected, the first contained starting material (0.5 L), fraction contained the title compound (2 L). The second fraction was concentrated in vacuo to dryness. The resulting foam was suspended in Et2O (0.12 L) and sonicated until all the material was converted into a homogenous suspension of fine yellow precipitate. 6-Methyl-N5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)-N1-(2-methylbenzo[d]thiazol-5-yl)isoquinoline-1,5-diamine was isolated by filtration as a light yellow powder (2.35 g, 28% yield). MS (M+H)+ 505.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][CH2:7][C:8](Br)=[O:9].[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>O>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:8](=[O:9])[CH2:7][Br:6])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Br)CBr
Reactant: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CN(C(=O)CBr)c1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
1.08 g of sodium bicarbonate (12.9 mmol) and 1.0 ml of bromoacetyl bromide (11.3 mmol) were added to a solution of 4.00 g of [2-(2-benzyloxyphenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (10a) (10.7 mmol) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=2/1) to obtain 4.86 g of the title compound (yield: 92%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCO.CCOC(C)=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a suspension of 2-aminoindane hydrochloride (5.0g, 29.5 mmol) and powdered K2CO3 (8.3 g, 60.0 mmol) in absolute EtOH (30 mL) was added tert-butyl bromoacetate (4.4 mL, 29.5 mmol). After stirring for 10 min at rt the reaction was heated to 45° C. and stirred for 2 hr. The reaction was cooled to rt, diluted with EtOAc, filtered and concentrated. Chromatography of the residue on silica gel (elution with 20% EtOAc:hexane) provided 4.7g of compound 721 as a white crystalline solid. ##STR100##
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[BH4-].[Na+]>CO>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH:2]([CH3:4])[CH3:1])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(C)=O
Reactant: NCCCNc1ccc2ncc(Br)n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)NCCCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
Acetone [67-64-1] (2.0 mL, 43.5 mmol), then powdered, activated, 4 Angstrom molecular sieve were added to a solution of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)propane-1,3-diamine (367.2 mg, 1.4 mmol) in methanol (4.8 mL). The reaction vessel was closed and the mixture allowed to rapidly stir, at ambient temperature, for 17 h then its content rapidly transferred into a stirring suspension of sodium borohydride [16940-66-2] (0.3 g, 6.9 mmol) in methanol (50 mL). After 1 h the mixture was gravity filtered and the filtrate evaporated. The crude product was then taken up in ethyl acetate, washed with brine, dried (MgSO4) and evaporated to provide 196.9 mg of yellow solid. LRMS (ESI) m/z 312.0/314.0 [(M+H)]+, calc'd for C12H18BrN5: 312.21.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6](Cl)=[N:7][C:8]=1[Cl:9])#[N:2].[CH3:12][OH:13]>>[C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6]([O:13][CH3:12])=[N:7][C:8]=1[Cl:9])#[N:2]
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CO
Product: COc1nc(Cl)c(C#N)c(Cl)n1

Procedure:
from 5-cyano-2,4,6-trichloro-pyrimidine and methanol (reaction time: 20 hours; reaction temperature: 65°C; without potassium carbonate).