Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23]C(=O)OCC=C)[CH:22]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:30])=[C:21]([CH:22]=2)[NH2:23])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of 2-propen-1-yl {5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (35 g, 78.4 mmol) in DCM (400 mL), HOAc (11.3 g, 188 mmol), Pd(PPh3)2Cl2 (1.1 g, 1.57 mmol) were added. Then tri-n-butyl tin hydride (34.2 g, 117 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (400 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (500 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound (18.3 g, 64.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.5 Hz, 1H), 6.96-7.03 (m, 3H), 6.78-6.83 (m, 1H), 2.30-2.60 (br, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1>>[CH3:1][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)=[CH:14][CH:15]=1)([CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Clc1cnccn1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2cnccn2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate and chloropyrazine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:20])=[O:7]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
A reactor is charged with 1 g (4.9 mmol) of 3-(trifluoromethyl)-4-methylbenzoic acid in 10 ml methanol in the presence of a catalytic amount of sulphuric acid. The mixture is heated for 6 hours at reflux. The solvent is then evaporated under reduced pressure and 100 ml of a saturated sodium bicarbonate solution is added to the mixture. The solution is extracted by 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure to give the expected product (1 g, 95%).
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([S:10][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][C:18]#[CH:19])=[CH:8][CH:7]=1.[CH2:22]([O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31]I)[CH3:23].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH2:22]([O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][C:19]#[C:18][CH2:17][C:16]#[C:15][CH2:14][C:13]#[C:12][CH2:11][S:10][C:9]1[CH:20]=[CH:21][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CCOC(=O)CCCC#CCI
Reactant: C#CCC#CCC#CCSc1ccc(C)cc1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CCCC#CCC#CCC#CCC#CCSc1ccc(C)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
12.03 ml (6.077 g, 0.0455 mol) of 3.8N ethylmagnesium bromide in ether was added dropwise to a solution of 9.65 g (0.0379 mol) of 9-(p-methylthiophenoxy)-1,4,7-nonatriyne in 80 ml of anhydrous tetrahydrofuran. The temperature was maintained at -10° C. The reaction mixture was stirred for 1 hour further at 0° C., allowed to warm to room temperature, and then 374 mg of cuprous cyanide were added. The mixture was stirred for 20 additional minutes, heated to 40° C. and then treated with 13.83 g (49.38 mmol) of 7-iodo-5-heptynoic acid ethyl ester in 30 ml of anhydrous tetrahydrofuran.The resulting mixture was stirred for 3 additional hours at 40° C., then poured on to 300 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml), the combined extract was concentrated to a small volume and washed several times with Versene solution and water, dried and evaporated in vacuo. The crude material was purified by column chromatography on 125 g of silica gel, using hexane:ethyl acetate (95:5) as eluant, to obtain 16-(p-methylthiophenoxy)-hexadeca-5,8,11,14-tetraynoic acid ethyl ester, as an oil. The product was stored in dry ice.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:31][CH3:32].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:14]([S:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:27][CH2:26]3)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)(C)c2cnc(SCC3CCNCC3)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)c2cnc(SCC3CCN(S(C)(=O)=O)CC3)n2-c2ccc(F)cc2)ccc1Cl
Yield: 74.6 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)piperidine (0.154 g, 0.33 mmol) and triethylamine (0.089 mL, 0.65 mmol) in DCM (2 mL) was added mesyl chloride (0.027 mL, 0.34 mmol). After 2 h the reaction was concentrated in vacuo and purified by column chromatography, using Hex:EtOAc as eluents, to afford the title compound (0.136 g) as a white solid. MS (EI) m/z 552 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[N:15][C:16]([C@@H:19]([NH2:21])[CH3:20])=[N:17][CH:18]=1.[F-].[Cs+]>CS(C)=O>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][C@H:19]([C:16]3[N:17]=[CH:18][C:13]([F:12])=[CH:14][N:15]=3)[CH3:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: C[C@H](Nc1ccc2ncc(Br)n2n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 64 %

Procedure:
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (Preparation 1b, 0.2 g, 0.86 mmol), (1S)-1-(5-fluoropyrimidin-2-yl)ethanamine (prepared according to the method described in WO2006/82392A1, 0.24 g, 1.72 mmol), cesium fluoride (1.31 g, 8.60 mmol) and dimethylsulfoxide (5 mL) was heated at 180° C. for 2 hours in a sealed tube. The reaction was cooled down, filtered through Celite® eluting with ethyl acetate and the filtrate was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (40-70% acetone in hexanes) to give the title compound (0.11 g, 64%) as a brown foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][CH2:2][C:3]1([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2(CO)CCOCC2)c2nc(C3CC3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1(CO)CCOCC1)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (4-hydroxymethyl-tetrahydro-pyran-4-yl)-amide (0.15 g, 0.33 mmol) in CH2Cl2 (7.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was dissolved in MeOH (10 mL) and H2O (1 mL) and Et3N (2 mL) were added. The reaction mixture was stirred at room temperature overnight then concentrated. The residue was triturated with Et2O to afford 96 mg (92%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (4-hydroxymethyl-tetrahydro-pyran-4-yl)-amide as an off-white solid. MS: (M+H)+=317; mp=294.0-296.0.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Cl:11][CH2:12][CH2:13][CH2:14]Br.O>CN(C)C=O>[Cl:11][CH2:12][CH2:13][CH2:14][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: ClCCCBr
Reactant: Nc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1OCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a stirred suspension of sodium hydride (11.0 g, 230 mmol of a 50% oil dispersion) in dimethylformamide (250 ml), under nitrogen, was added, dropwise, 2-aminophenol (25.0 g, 230 mmol) dissolved in dimethylformamide (125 ml). After complete addition, the reaction was stirred at ambient temperature for 1 hour, and then it was cooled to 5° C. (ice bath). 3-Chloro-1-bromopropane (36.2 g, 230 mmol) in dimethylformamide (50 ml) was added, dropwise, so that the temperature did not go above 8° C. The reaction was stirred for 4 hours and then permitted to stand at ambient temperature for 16 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 25.4 g of a reddish, dark oil. About 12.0 g of the oil was chromatographed on HPLC columns. Concentration of the largest fractions gave 5.4 g of 2-(3-chloropropoxy) aniline as an oil.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([CH3:13])([CH3:14])[O:11][C:10]1=[O:15])=[O:26]
Reactant: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N1C(=O)OC(C)(C)[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Reaction of the auxiliary (10) (0.085 g, 0.415 mmol) in solution in tetrahydrofuran (2 ml) at -78° C. with butyllithium (1.6M, 0.262 ml, 0.419 mmol) and pivaloyl chloride (0.056 ml, 0.456 mmol) for 30 minutes and then at room temperature for 2 hours with work-up and flash column chromatography using 30% ethyl acetate/40-60 petroleum ether furnished the title compound (19) as an oil (0.104 g, 87%); νmax (CDCl3) 1742 cm-1 ; δH (CDCl3 ; 300 MHz) 1.30 (3H, s, C(CH3)2), 1.34 (6H, s, C(CH3)3), 1.35 (3H, s, C(CH3)2), 2.86 (1H, dd, J=9.3 and 14.2, CH2Ph), 3.05 (1H, dd, J=4.1 and 14.2, CH2Ph), 4.53 (1H, dd, J=4.2 and 9.3, CHCH2), 7.18-7.28 (5H, m, ArCH); δC (125 MHz; CDCl3) 22.10 (CH3), 26.29 (CH3), 28.07 (CH3), 35.24 (CH2), 41.68 (C), 65.47 (CH), 81.80 (C), 126.94 (CH), 128.76 (CH), 129.38 (CH), 137.19 (C), 152.03 (CO), 179.49 (CO); m/z (CI+, NH3) 290 (M+ +1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[O:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:15])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl>C(O)(C)C.C([O-])(O)=O.[Na+]>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[O:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC2OC(C1)c1cc(N)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCN1CC2OC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 120 °C
Yield: 26.8 %

Procedure:
10-Ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (100 mg, 0.49 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (200 mg, 0.67 mmol) were combined with 4 N HCl (0.14 mL, 0.56 mmol) in isopropanol (4 mL) and heated in a microwave at 120° C. for 20 min. The resulting mixture was diluted with saturated aqueous NaHCO3 (3 mL), extracted with CH2Cl2 (3×5 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (0-10% MeOH in CH2Cl2) to obtain 2-[5-Chloro-2-(10-ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a light yellow solid (61 mg, 27%). 1HNMR (400 MHz, DMSO-d6) δ 11.5 (s, 1H), 9.5 (s, 1H), 8.8-8.7 (m, 2H), 8.2 (s, 1H), 7.8 (d, 1H, J=8.1 Hz), 7.6 (s, 1H), 7.5 (appt t, 1H, J=8.1 Hz), 7.4 (d, 1H, J=7.8 Hz), 7.2-7.1 (m, 2H), 5.0 (m, 2H), 2.8 (d, 3H, J=4.3 Hz), 2.7 (m, 2H), 2.4 (m, 2H), 2.3 (q, 2H, J=7.2 Hz), 0.8 (t, 3H, J=7.2 Hz); MS (m/e) 465 (M+1); mp 122-126° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([N+:9]([O-])=O)([CH2:6][NH:7][CH3:8])[CH2:4][OH:5]>CO.[Ni].O>[ClH:1].[NH2:9][C:3]([CH3:2])([CH2:6][NH:7][CH3:8])[CH2:4][OH:5]
Reactant: CNCC(C)(CO)[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNCC(C)(N)CO
Reaction time: 48 h
Yield: 163.6 %

Procedure:
To a solution of 2-methyl-3-(methylamino)-2-nitropropan-1-ol hydrochloride (5.4 g) in methanol (32 ml) was added a slurry of Raney Nickel in H2O (1.5 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 48 h. The mixture was filtered through Celite and concentrated in vacuo to give a crude liquid (7.4 g, >100%), which was used directly in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H), 2.26 (s, 3H), 2.99 (s, 2H), 3.41-3.44 (d, J=11.6, 1 H), 3.48-3.51 (d, J=11.6 Hz, 1H). LRMS (ESI/APCI) m/z 145 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:18])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.Cl>[Br:26][C:24]1[N:25]=[C:20]([NH:18][C:15]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: NC1(c2ccccc2OCc2ccccc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (Example 167a, 5 g) in dioxane (200 mL) was treated with 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252g, 7.5 g) and N-ethyldiisopropylamine (5.36 mL) under nitrogen. The resulting solution was stirred at 100° C. for 8 h. The cooled reaction mixture was diluted with 2M HCl (300 mL), and extracted with ether (3×300 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography eluting with 20% ethyl acetate in iso-hexane) gave the subtitle compound. (9.20 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:25]>CC(O)C>[NH2:25][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(N)ncnc32)C1
Yield: 78 %

Procedure:
A solution of (R)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.0 g, 4.32 mmol) in IPA saturated with NH3 (20 mL) was stirred at 100° C. for 12 h in a 100 mL of autoclave. The organic layer was concentrated and purified on silica gel chromatography (eluted with PE:EtOAc=1:1) to afford (R)-tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.5 g, 78% in yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:17]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(#N)C>[Cl:17][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[NH2:16])[N:7]([C:5](=[O:6])[CH2:4][N:2]([CH3:1])[CH3:3])[CH2:8][CH2:9]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)CC(=O)N1CCc2ccc(N)cc21
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)CC(=O)N1CCc2cc(Cl)c(N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.7 %

Procedure:
A solution of 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (3.0 g, 13.68 mmol) in acetonitrile (150 mL) was treated with N-chlorosuccinimide (2.010 g, 15.05 mmol) and stirred at room temperature for 15 minutes. The solution was poured into chloroform/saturated sodium bicarbonate (aq.) and the organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-chloro-1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.510 g, 15% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H), 7.01 (s, 1 H), 5.21 (s, 2 H), 4.08 (t, J=8.33 Hz, 2 H), 3.16 (s, 2 H), 2.95 (t, J=8.33 Hz, 2 H), 2.25 (s, 6 H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](CC(O)=O)[CH:8]=1>C(Cl)Cl.CN(C=O)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:1][C:2]([Cl:4])=[O:3])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (211 μl; 2.23 mmol; 1.2 eq.) was added to a suspension of 3-pyridineacetic acid (255 mg; 1.86 mmol; 1.0 eq.) in DCM/DMF (5 mL:3 μL) maintained at 0° C. under nitrogen atmosphere. The reaction mixture was then stirred at rt for 1 h. It was then concentrated under reduced pressure. The solid obtained was used as such in amidation reactions.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:26]([O:25][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24])[C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NOC(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)c1ccccc1)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl {[2-(methylsulfonyl)phenyl]sulfonyl}[(phenylcarbonyl)oxy]carbamate (47) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino benzoate according to Scheme 2. (1.7 g, 91%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.25-8.45 (2H, m), 8.03-8.20 (4H, m), 7.77-7.93 (1H, m), 7.59-7.73 (2H, m), 3.48 (3H, s), 1.29 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12](O)[C:11]1=[O:23])=[O:4].P(Br)(Br)[Br:31]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([Br:31])[C:11]1=[O:23])=[O:4]
Reactant: BrP(Br)Br
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](Br)CCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of 3-((3S,6S)-6-cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (200 mg, 0.75 mmol, 1 equiv) in CH2Cl2 (1.0 mL) was added PBr3 (1.0 M in CH2Cl2, 0.09 ml, 0.38 mmol, 0.8 equiv.) at room temperature and the resulting solution was stirred at room temperature for 18 hours. The reaction solution was then concentrated under vacuum and the residue was purified by silica gel column chromatography, (EtOAc/Heptane, 10%˜60%) to give product 166 mg (yield 76%). MS: 481 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][CH2:16]Br.C(Cl)Cl>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[Br:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: BrCCc1ccccc1Br
Reactant: Cc1[nH]c2ncccc2c1C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc2n(CCc3ccccc3Br)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (554 mg, 3.8 mmol) and o-bromophenethyl bromide (1000 mg, 3.8 mmol) in 11 ml CH3CN was refluxed for 16 h. The solvent was evaporated and the residue chromatographed (silica, CH2Cl2 /MeOH; 9/1) to give 546 mg enriched product. Pure 2,3-dimethyl-7-(o-bromophenethyl) pyrrolo[2,3-b]pyridine was obtained by a second chromatography (silica, CH2Cl2 saturated with NH3/petroleum ether; 7/3). A deaerated solution of 2,3-dimethyl-7- (o-bromophenethyl) pyrrolo[2,3-b]pyridine (249 mg, 0.76 mmol) in 25 ml dry THF was cooled to -78° C. and treated with 1.6M n-BuLi in hexane (576 μl, 0.91 mmol). After 3 min a vigurous stream of CO2 (g) was bubbled through the solution. The solution was allowed to warm to room temperature and 1.5 ml H2O was added. The solvent was evaporated and the residue chromatographed (reversed phase silica, MeOH/H2O; 6/4) yielding 51 mg (23%) pure amino acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][CH3:27].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[Br:18][C:19]1[C:20]([O:26][CH3:27])=[CH:21][C:22]([Cl:25])=[C:23]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=2)=[O:9])[CH:24]=1
Reactant: COc1cc(Cl)ccc1Br
Reactant: CCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-ethyl benzoic acid (AQ) (0.50 g, 3.33 mmol) in dry dichloromethane (20 mL) was added dropwise oxalyl chloride (0.32 mL, 3.68 mmol) followed by N,N-dimethylformamide (0.1 mL). After being stirred for 2 h at room temperature, the reaction mixture was evaporated and the residue was dissolved in dry dichloromethane (20 mL) at room temperature under agron. After cooling to −5° C., 1-bromo-4-chloro-2-methoxybenzene (0.6 g, 2.78 mmol) was added. Then AlCl3 (0.43 g, 3.33 mmol) was added portionwise and the reaction temperature was kept between −5° C. and 0° C. After being stirred at room temperature for four hours, the reaction mixture was poured onto ice water and extracted with dichloromethane (80 mL). The combined organic layers were washed with 1 M HCl (10 mL), water (10 mL) and brine (10 mL), and then dried over anhydrous Na2SO4 Concentration under reduced pressure gave AR as a white solid. Yield: 0.5 g (52.3%). 1H-NMR (CDCl3, 400 MHz): δ 7.75 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 6.98 (s, 1H), 3.99 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).