Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH3:7])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH:6]([C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH3:7])=[N+:26]=[N-:27]
Reactant: CC(OS(C)(=O)=O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the crude 1-[6-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethyl methanesulfonate in N,N-dimethylformamide (1 mL) was added sodium azide (57 mg, 0.88 mmol). The reaction was stirred at room temperature for 2 hours, quenched with water, and then extracted with EtOAc. The extracts were combined, washed with brine, dried over MgSO4 and concentrated to give the desired azide (55 mg), which was used directly in the next step. LCMS calculated for C16H12ClFN (M-N3)+: m/z=272.1. Found: 271.9.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CO>ClCCl>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH2:6]1
Reactant: CC(=O)OC1CCN(CC#CCN2CCCC2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCN1CC#CCN1CCC(O)C1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of 800 mg of (racemic)-1-[4-[3-(acetyloxy)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone, 595 mg of sodium carbonate and 40 ml of methanol was stirred overnight. An equal volume of dichloromethane was added and this mixture was filtered. The filtrate was concentrated and the residue was diluted with dichloromethane, filtered and concentrated in vacuo. The residue was purified by chromatography (alumina), giving 470 mg of the desired product as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.C[N:14](C=O)C>>[F:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([NH2:14])[C:7]2=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: Fc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Product: Nn1ccc2cc(F)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A suspension of NaH (4.4 g, 110 mmol, 60% in mineral oil) in DMF (37 mL) at 0° C. is treated with 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 7.4 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (4.2 g, 37 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30%-70% EtOAc in heptane to afford 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (980 mg, 88%). MS: 152 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.60 (m, 1H), 7.42 (m, 1H), 6.36 (s, 1H), 5.01 (s, NH2, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[O:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
To a stirred solution of 7.48 g (40 mmoles) of p-bromobenzyl alcohol and 6.07 g (60 mmoles) of triethylamine in 70 mL of sieve dried DMF at 0° C. was added 14.3 g (52 mmoles) of neat t-butyldiphenylsilylchloride. The ice-water bath was removed and the mixture was stirred further for 20 hours.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:16]([OH:18])=[O:17])=[C:11]3[C:6]([CH:7]=[C:8]4[CH:22]=[CH:21][CH:20]=[CH:19][C:9]4=[CH:10]3)=[N:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.[CH2:30]([N:32]([CH2:35][CH2:36]Br)[CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:35][CH2:36][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:16]([O:18][CH2:31][CH2:30][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:17])=[C:11]3[C:6]([CH:7]=[C:8]4[CH:22]=[CH:21][CH:20]=[CH:19][C:9]4=[CH:10]3)=[N:5][C:4]=2[CH:3]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: CCN(CC)CCBr
Reactant: O=C(O)c1c2ccc(O)cc2nc2cc3ccccc3cc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CC)CCOC(=O)c1c2ccc(OCCN(CC)CC)cc2nc2cc3ccccc3cc12

Procedure:
treating 3-hydroxy-benz[b]acridine-12-carboxylic acid with cesium carbonate and diethylaminoethyl bromide hydrobromide to produce N,N-diethylaminoethyl 3-(N,N-diethylamino)ethoxy-benz[b]acridine-12-carboxylate;
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[N:18]1(C(N)=O)[CH2:22]CC[CH2:19]1>>[CH3:19][N:18]([CH3:22])[C:13](=[O:14])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)C2CC2)cc1
Reactant: NC(=O)N1CCCC1
Product: CN(C)C(=O)C(C)(C)c1ccc(C(=O)C2CC2)cc1

Procedure:
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid, pyrrolidineamide;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:19]#[N:20])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:19]#[N:20])[CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: N#CC(CCC1CCNCC1)c1ccc(Cl)c(Cl)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC(CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
25 g of 1-(3,4-dichlorophenyl)-3-(4-piperidinyl)-1-cyanopropane hydrochloride (Example 1B) are dissolved in 400 ml of CH2Cl2. 22 g of trityl chloride and 21 ml of triethylamine are added dropwise to the solution. The reaction mixture is left for 2 hours without stirring, and washed successively with H2O, an aqueous solution buffered to pH=2, and a solution saturated with NaCl. It is dried over MgSO4 and evaporated. The residue is chromatographed on silica gel, eluent: heptane/ethyl acetate 9:1 (v/v). 39 g of oil are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1.[C:15]([Cu])#[N:16]>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)[CH:4]=1
Reactant: Cn1nnc(-c2cc(F)ccc2Br)n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2cc(F)ccc2C#N)n1
Temperature: 105 °C
Yield: 73.8 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-2-methyl-2H-tetrazole (650 mg, 2.53 mmol) and CuCN (224 mg, 2.5 mmol) in dimethylformamide (4 mL) was placed in a sealed tube and heated at 100-110° C. for 20 hrs. After cooling, the insoluble material was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with aq. 4N HCl and dil. NH4OH, then dried (MgSO4), filtered, and concentrated. The residual solid was purified by column chromatography (SiO2, CH2Cl2) to obtain 375 mg (Yield 73%) of the title compound as an off-white solid; 1H NMR (500 MHz, CDCl3) δ ppm: 4.48 (3H, s) 7.29 (1H, dd, J=7.6, 2.8 Hz) 7.85 (1H, dd, J=8.6, 5.2 Hz) 8.00 (1H, dd, J=9.0, 2.6 Hz); LC/MS m/z 204.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:33]([O:37][C:38]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[CH2:49]Cl)=[O:39])([CH3:36])([CH3:35])[CH3:34].[I-].[K+]>CC#N>[C:33]([O:37][C:38]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[CH2:49][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[CH:13]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][CH2:15][CH2:14]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCOc2cccnc21
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCOc2cccnc21
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of [4-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino)-butyl]-carbamic acid tert-butyl ester (329 mg, 1.02 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.28 mL, 1.63 mmol) followed by 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (328 mg, 1.23 mmol) and potassium iodide (20 mg, 0.1 mmol). The resultant mixture was heated to 60° C. for 16 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (25 mL) and saturated aqueous NaHCO3 (20 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 95:4:1) provided 2-{[(4-tert-Butoxycarbonylamino-butyl)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (380 mg, 67%) as a white foam.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH3:35]>>[O:31]1[CH2:32][CH2:33][N:28]([C:10]2[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:35])[CH:7]=3)[N:9]=2)[CH2:29][CH2:30]1
Reactant: N
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(F)c4)nc(N4CCOCC4)c3s2)CC1
Agent: [OH-]
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(N)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(2-Fluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (107 mg) was heated in ammonia hydroxide (90 ml) in a sealed stainless steel pressurized vessel at 150° C. for 5 days. Extraction into chloroform and purification on silica afforded 314 (57 mg). NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.55 (2H, br s), 7.36 (1H, s), 7.54 (1H, s), 7.65 (1H, d, J=5.3), 8.21 (1H, d, J=5.3). MS (ESI+): MH+ 490.16 (74%)
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CN(C)CCN
Agent: Cl
Product: CN(C)CCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.7 mg (0.23 mmol) of N-(2-aminoethyl)-N,N-dimethylamine are reacted together by general method E. 42.5 mg (64.5% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[N:7][CH:6]=1.C=O.[C:27]([O-])([O-])=[O:28].[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)=[O:12])=[N:7][CH:6]=1)[CH2:27][OH:28]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Agent: C=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Temperature: 50 °C

Procedure:
A mixture of {2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-acetic acid methyl ester (4.17 mmol), paraformaldehyde (0.95 equiv.) and K2CO3 (0.95 equiv.) in DMSO (10.0 mL) was heated at 50° C. for 1.5 hours. The reaction was cooled, diluted with EtOAc, washed with water, dried and concentrated to give a residue that was purified by flash column chromatography on silica gel (0 to 6% MeOH in EtOAc) to provide 3-hydroxy-2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-propionic acid methyl ester (compound 73.1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 72.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid (143 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (75 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 24 h. At this time, the reaction was diluted with methylene chloride (5 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (133 mg, 72%) as a white solid: mp 170-172° C.; EI-HRMS m/e calcd for C21H24N2O2S (M+) 368.1558, found 368.1556.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH:9]([OH:11])[CH3:10].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:11][CH:9]([CH3:10])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (2.86 ml, 36.9 mmol) was added dropwise to an ice-cooled solution of 1-methoxy-2-propanol (3 ml, 30.7 mmol) and triethylamine (10.27 ml, 73.7 mmol) in dichloromethane (150 ml), and the reaction stirred at room temperature for 18 hours. The mixture was washed with water, then 2M hydrochloric acid, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow oil, 5.24 g.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([NH2:16])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:3][CH2:2][CH2:1][C:9]1([CH3:8])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1)(=[O:15])[CH3:14]
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(N)=O
Solvent: c1ccccc1
Product: CC(=O)NCCCC1(C)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of indene-3-ethanol (4.2 g) and N-(4-oxopentyl(acetamide (3.7 g), described by L. P. Kuhn et al., J. Am. Chem. Soc., 89, 3858 (1967), in 300 ml of dry benzene is stirred and heated at reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated to yield 1-[3-(acetamido)propyl]-1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran, νmaxCHCl3 1650 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.O.C(=O)([O-])O.[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>O1CCCC1>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=2)[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(N)cc1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 5-amino-2-methylphenol (7.38 g, 59.9 mmol) in tetrahydrofuran (30 mL) was added water (30 mL) in which sodium hydrogen carbonate (6.00 g, 71.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. 3-(Trifluoromethyl)benzoyl chloride (15.0 g, 71.9 mmol) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 24 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and was filtrated, and the solvent was evaporated under reduced pressure. A mixture of the obtained residue, methanol (30 mL) and 2N aqueous sodium hydroxide solution (30 mL) was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad with two layers of silica gel and celite. The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (14.8 g, 84%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1>O1CCCC1.O1CCOCC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[N:2]([CH3:3])[CH3:1])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: CNC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)c1ncnc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.40 ml of a solution of dimethylamine in tetrahydrofuran (2 M) are added to 500 mg 4-chloro-8-nitro-quinazoline in 3 ml dioxane and the reaction mixture is stirred for one hour at ambient temperature, then another 1 ml of a solution of dimethylamine in tetrahydrofuran (2 M) is added. The reaction mixture is stirred overnight and then evaporated down in vacuo. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (65:35 to 40:60).
Reaction SMILES: [CH2:1]([N:8]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[NH:9]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([N:8]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N(N)Cc1ccccc1
Yield: 91.6 %

Procedure:
A solution of of 2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide (2.8 g, 9.6 mmol) in 50% trifluoroacetic acid in dichloromethane (10 ml) was stirred for 10 min at room temperature. Then saturated sodium bicarbonate was added until pH>7 and the aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The obtained oil was chromatographed on silica (100 g) with ethyl acetate as eluent to give 1.7 g of 2-benzyl-4-ethylsemicarbazide.
Reaction SMILES: CO[CH:3]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])[S:10][C:6]=2[CH:5]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CC#N>[NH:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([CH2:3][C:4]2[CH:20]=[CH:19][C:7]3[N:8]=[C:9]([NH:11][C@@H:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]4[OH:18])[S:10][C:6]=3[CH:5]=2)=[CH:22]1
Reactant: COC(c1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3c[nH]c4ncccc34)cc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a solution of (1R,2R)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 0.049 mmol) from Step 3 of Example 12 in CH3CN (10 mL) were added triethylsilane (11.4 mg, 0.092 mmol) and TFA (10.4 mg, 0.092 mmol) at rt. The mixture was stirred at 60° C. overnight. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (5.7 mg, 31%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 11.71 (br s, 1H), 9.56 (br s, 1H), 8.23 (d, J=4.1 Hz, 1H), 7.93 (d, J=7.0 Hz, 1H), 7.70 (s, 1H), 7.26-7.42 (m, 3H), 7.07 (dd, J=4.9, 7.9 Hz, 1H), 4.11 (s, 2H), 3.53 (br s, 1H), 3.27-3.43 (m, 2H), 1.83-2.12 (m, 2H), 1.66 (br s, 2H), 1.27 (br s, 4H). LCMS (ESI) m/z 379 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11]>C1COCC1>[C:1]([NH:5][S:10]([CH2:9][CH2:8][CH2:7][Cl:6])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: -20 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to −20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%).