Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](=[C:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH3:5].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[NH:26])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:12](=[O:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([S:4][CH3:5])[N:26]=[C:25]2[C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SC)SC
Reactant: CSc1ccc(C(=N)Nc2ccc(C)cc2)cc1
Product: CCOC(=O)c1c(SC)nc(-c2ccc(SC)cc2)n(-c2ccc(C)cc2)c1=O
Temperature: 115 °C
Yield: 20.2 %

Procedure:
A mixture of diethyl [bis(methylthio)methylene]malonate (2.64 g, 10 mmol) and N-(4-methylphenyl)-4-(methylthio)benzenecarboximidamide (2.6 g, 10 mmol) (prepared according to the procedure described in preparation 6) was heated at 110-120° C. for 2 hours. The gummy mass thus obtained was purified by column chromatography to give the title compound (0.86 g, yield 20.2%, mp 153-155° C., purity 99.81% by HPLC). 1H-NMR (CDCl3):δ 1.36-1.39 (t, 3H), 2.33 (s, 3H), 2.44 (s, 3H), 2.55 (s, 3H), 4.37-4.42 (q, 2H), 7.0-7.05 (m, 4H), 7.13-7.15 (d, 2H), 7.25-7.27 (d, 2H). IR (KBr) cm−1: 2981, 2924, 1693 (—C═O). MS m/z:427.1(M+)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[C:21]([N:31]1[CH2:49][CH2:48][CH2:47][C@H:32]1[C:33]([NH:35][C:36]([C:44](O)=[O:45])=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:44](=[O:45])[C:36](=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:35][C:33](=[O:34])[C@@H:32]1[CH2:47][CH2:48][CH2:49][N:31]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of 0.759 g (0.0036 mole) of L-phenylalanine methyl ester hydrochloride and 40 ml of ethyl acetate was cooled in an ice-bath and 15 ml of cold 505 potassium carbonate solution was added. The mixture was equilibrated, and the ethyl acetate layer was separated and dried over anhydrous Na2SO4 at 0°. To the solution 1.129 g (0.003 mole) of the azlactone of N-carbobenzoxy-L-prolyl-dehydrophenylalanine was added. The reaction mixture was then refluxed for 8 hours, cooled and washed with N-hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residual crystals were recrystallized from ethyl acetate/petroleum ether giving 1.473 g (88%) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine methyl ester, mp 161°-163.5°, RfA 0.95, [α]D26 =-94.3° (c, 1% in EtOH); ir (CHCl3) 1735 (C=) 1690-1670 (C=O), 1630 cm-1 (C=C); NMR (CDCl3) δ1.5-2.4 (m, 4H, Pro ring), 3.0-3.33 (m, 2H, --CHCH2Ph), 3.33-3.57 (m, 2H, Pro ring) 3.63 (s, 3H, --COOCH3), 4.17-4.53 (m, 1H, --CH-CH2Ph), 4.67-5.0 (m, 1H, Pro ring), 5.02 (br.s., 2H>NOCOCH2Ph) 6.83-7.47 (m, 11H, ArH and PhCH=C<), 7.9-8.1 ppm (b, 2 H, NH, exchange by D2O).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH:4]([NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1)[C:5](O)=[O:6].Cl.[CH2:31]([O:38][C:39](=[O:45])[CH2:40][CH:41]([OH:44])[CH2:42][NH2:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[CH2:31]([O:38][C:39](=[O:45])[CH2:40][CH:41]([OH:44])[CH2:42][NH:43][C:5](=[O:6])[CH:4]([NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1)[CH2:3][CH:2]([CH3:29])[CH3:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC(O)CC(=O)OCc1ccccc1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)NCC(O)CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 4-methyl-2-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-pentanoic acid (3.6 g), 4-amino-3-hydroxy-butyric acid benzyl ester hydrochloride (1.6 g), triethylamine (1 ml) and HOBT (1.06 g) in DMF (50 ml) at room temperature was added EDCl (1.63 g). After stirring 16 h the mixture was poured into 1500 ml ice-water and stirred for 20 min. The resulting ppt was filtered and dried to give a creme colored solid. Recrystallization from EtOAc gave 2.1 g of the title compound as a white solid. MS [M+1]+ 589.2; 1H nmr (400 MHz, DMSO-d6) δ0.73-0.81 (m, 6H), 1.37-1.49 (m, 3H), 2.19 (s, 3H), 2.20-2.28 (m, 1H), 2.46-2.49 (m, 1H), 2.99-3.09 (m, 2H), 3.33 (q, J=13.8 Hz, 2H), 3.90 (m, 1H), 4.19-4.23 (m, 1H), 5.05 (m , 2H), 6.88 (t, 1H), 7.06-7.12 (m, 4H), 7.26-7.34 (m, 6H), 7.75 (d, J=8.1 Hz, 1H), 7.92 (dt, 1H), 8.06 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 9.13 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21](=O)[C:22]([F:25])([F:24])[F:23])C>C(O)C>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:21](=[O:20])[C:22]([F:25])([F:24])[F:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Product: O=C(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g (421.5 mmol) of L-glutamic acid-5-benzylester is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:47].O1CCOCC1>CO>[ClH:47].[ClH:47].[ClH:47].[ClH:47].[NH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Reaction time: 23 h
Yield: 88 %

Procedure:
Methyl 5-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]pyridine-2-carboxylate (52 mg, 0.085 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 23 hours. The mixture was concentrated to afford the desired product (49 mg, 88%) as an orange solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.70-8.68 (m, 1H), 8.65 (br s, 1H), 8.63 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.0 Hz and 2.3 Hz, 1H), 8.10 (dd, J=4.6 Hz and 1.7 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.39-7.35 (m, 3H), 7.29 (d, J=7.4 Hz, 1H), 7.12 (td, J=8.0 Hz and 1.1 Hz, 1H), 6.91 (dd, J=8.6 Hz and 1.1 Hz, 1H), 6.73 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.84 (s, 3H), 2.60-2.56 (m, 2H), 2.55-2.50 (m, 2H), 2.21-2.13 (m, 1H), 1.86-1.77 (m, 1H). LCMS: 515 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:19][CH3:20])=[CH:11][C:12]([I:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:19][CH3:20])=[CH:11][C:12]([I:18])=[C:13]([C:14]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:16])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(I)c(C(=O)O)cc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(I)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-benzyloxy-2-iodo-4-methoxybenzoic acid (reference example 5-2) (1.92 g), piperidine (0.74 mL) and N,N-dimethylforamide (12 mL) was added 1-hydroxybenzotriazole (676 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.44 g) at room temperature. The mixture was stirred at room temperature for 6 hours. After addition of ethyl acetate, the mixture was poured into 2 mol/L hydrochloric acid. The organic layer was washed with water, an aqueous solution of sodium bicarbonate, and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The mixture of the residue, aminopropylsilicagel and dichloromethane was stirred for 30 minutes. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (2.13 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCCC1
Yield: 76.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with cyclohexanecarbonyl chloride (0.55 mL, 4.1 mmol) to provide 1.07 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecarboxamide as an off white solid, m.p. 191.6-192.6° C. Analysis: Calculated for C22H29N5O.0.25H2O: % C, 68.81; % H, 7.74; % N, 18.24; Found: % C, 68.85; % H, 7.75; % N, 17.95.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][C:5]=2[CH:4]=1)[NH2:2].[CH3:22][C:23]([CH3:25])=O>>[C:23](=[N:2][NH:1][C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][C:5]=2[CH:4]=1)([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: CCCCCCCC(=O)N1CCc2nnc(NN)cc2C1
Product: CCCCCCCC(=O)N1CCc2nnc(NN=C(C)C)cc2C1
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g of crude semicrystalline 3-hydrazino-6-octanoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 50 cc of acetone is heated to the boil at reflux while stirring for 30 minutes. The title compound has a M.P. of 118°-121° (decomp., from light gasoline).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH:29]1([NH:35][C:36]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C@:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]1(CN2CCN(C(=O)NC3CCCCC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
(S)-2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol) was dissoloved in a mixture of methylene chloride (15 ml) and triethylamine (2 ml, 14.35 mmol). To the solution, cyclohexyl isocyanate (120 mg, 0.96 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid cyclohexylamide (164 mg, 47%) as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:25]=[CH:26][CH:27]=[C:15]([C:14]([F:13])([F:29])[F:28])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1

Procedure:
A solution of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma, 1.2 g, 6.97 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet, 1.57 g, 6.36 mmol) in DCM (10 mL) was treated with EDCI (Aldrich, 1.57 g, 6.36 mmol) and HOBT (Aldrich, 1.22 g, 6.36 mmol) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][S:5][C:6]1[N:7]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)([CH3:13])[CH3:12])=[CH:9][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Br:41]Br>C(Cl)Cl>[Br:41][C:9]1[N:10]=[C:6]([S:5][CH2:4][C:3]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:2]=2[Cl:1])[N:7]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:8]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:13])[CH3:12]
Reactant: BrBr
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1c(Br)nc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of 2-(2-chloro-6-fluorobenzylthio)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (950 mg, 1.81 mmol) and sodium carbonate (634 mg, 5.98 mmol) in DCM:H2O (5 mL:5 mL) was added bromine (0.1 mL, 2.00 mmol) dropwise at 0° C. The resulting mixture was stirred for 3 h and diluted with DCM (15 mL). The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified with flash chromatography to afford the title compound (970 mg, 89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.62 (s, 6H), 4.35 (s, 2H), 6.43 (m, 2H), 6.80 (t, 2H), 6.84 (dd, 1H), 6.95 (t, 1H), 6.99 (dd, 1H), 7.16 (m, 2H), 7.25 (t, 1H); MS (EI) m/z 602 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: CC1(C)CN(c2ncc(I)cc2F)C(=O)O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CN(c2ncc(C#Cc3ccccc3)cc2F)C(=O)O1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (12.5 mg, 17.9 μmol, 0.05 equiv.) was dissolved in 1 ml DMF. (120 mg, 357 μmol) 3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (Example 1, step 2) and phenylacetylene (72.9 mg, 78.4 μl, 714 μmol, 2 equiv.) were added at room temperature. Triethylamine (108 mg, 149 μl, 1.07 mmol, 3 equiv.), triphenylphosphine (2.81 mg, 10.7 μmol, 0.03 equiv.) and copper(I)iodide (2.04 mg, 10.7 μmol, 0.03 equiv.) were added and the mixture was stirred for 3 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 3-(3-fluoro-5-(phenylethynyl)pyridin-2-yl)-5,5-dimethyloxazolidin-2-one (96 mg, 309 μmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=311.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H-].[Na+].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][CH:14]=1.CO>C1COCC1>[N+:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH2:1])=[CH:14][CH:15]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cnccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnccc1COc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a solution of (3-amino-pyridin-4-yl)-methanol (13) (4.00 g, 32.2 mmol) in anhydrous THF (160 mL) at 0° C. was added sodium hydride (1.55 g, 38.7 mmol, 60 wt %). After stirring for 20 min, 1-fluoro-4-nitronaphthalene (14) (6.16 g, 32.2 mmol) was added, the ice bath was removed and the reaction mixture left to warm to RT and stirred for 12 hr. The reaction mixture was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 solution (150 mL). The remaining yellow solid was collected by filtration and washed sequentially with water (50 mL), MeOH (50 mL) and diethyl ether (100 mL) and was identified as the desired product by LC-MS and 1H NMR. The filtrate was returned to a separating funnel; the organic phase was collected and washed with brine (100 mL), dried and concentrated in vacuo to afford an orange residue. Trituration of the orange residue with MeOH (200 mL) afforded an orange solid which was washed with diethyl ether (200 mL). LC-MS and 1H NMR analysis of the orange solid was identical to that observed for the insoluble solid obtained earlier. The two products were combined to afford the title compound (15) (7.80 g, 77%): m/z 296 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]3[O:37][CH:38]=[C:39]([C:41]([O:43]C)=[O:42])[N:40]=3)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]3[O:37][CH:38]=[C:39]([C:41]([OH:43])=[O:42])[N:40]=3)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1coc(N[C@@H]2CCC[C@H](Nc3nc(-c4cn(S(=O)(=O)c5ccc(C)cc5)c5ncc(F)cc45)ncc3F)C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1coc(N[C@@H]2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(F)cc45)ncc3F)C2)n1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-[[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]amino]oxazole-4-carboxylate, 71a, (0.028 g, 0.045 mmol) in THF (1 mL) was added LiOH (1 mL of 1 M solution, 1.000 mmol) and the reaction mixture was warmed to 130° C. via microwave irradiation. After heating and stirring for 20 minutes, the mixture was cooled to room temperature. All volatiles were removed under a stream of nitrogen and heat. The crude residue was suspended in MeOH and a few drops of trifluoroacetic acid were added to protonate molecule (solution occurs). The mixture was filtered and purified by reverse phase HPLC (5-95% CH3CN/H2O) to afford 5 mg of the desired product as a TFA salt: 1H NMR (300 MHz, MeOD) δ 8.83 (s, 1H), 8.67-8.09 (m, 4H), 2.67 (s, 3H), 2.18 (m, 5H), 1.34 (d, J=29.6 Hz, 3H); LCMS RT=1.78 (M+1) 456.07.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[OH-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>O1CCOCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:2][N:3]2[CH2:4][CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)=[S:26])=[CH:20][CH:19]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: NN1CC=C(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(NC(=S)NN2CC=C(c3ccccc3)CC2)cc1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
To a stirred solution of N-amino-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.05 g) in a mixture of dioxane (10 ml) and water (5 ml) was added 1N sodium hydroxide solution (5 ml) under ice-bath cooling, and then a solution of 4-fluorophenyl isothiocyanate (1.15 g) in dioxane (5 ml) was added thereto. The mixture was stirred for 5 hours under ice-bath cooling. The reaction mixture was evaporated in vacuo and the residue was extracted several times with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give a crude product, which was recrystallized from ethyl acetate to give N-[[(4-fluorophenyl)thiocarbamoyl]amino]-4-phenyl-1,2,3,6-tetrahydropyridine (1.05 g).
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.O.[NH2:17][NH2:18]>CO>[NH:17]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)[NH2:18]
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC1=NCc2c[nH]c3cccc1c23
Reaction time: 8 h

Procedure:
A solution of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (10.0 g), described in Example 5, in methanol (100 ml) is combined with a solution of hydrazine hydrate (3 g) in methanol (150 ml). After boiling overnight the mixture is concentrated to half of its original volume and diluted with ether. The resulting precipitate is collected to give the title compound, mp 188° - 189°C, νmaxnujol 3370, 3325, 3150, 1628, 1583, 1540 and 1510 cm-1.