Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=C[CH:2]=1.[C:8](=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1>CN(C=O)C>[C:18]1([C:21]2[CH:22]=[CH:8][C:6]([C:1](=[S:7])[CH3:2])=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
Thiophenol (184 g) was gradually added dropwise to a suspension of 196 g of anhydrous potassium carbonate in 1,000 ml of DMF at room temperature, followed by dropwise addition of 200 g of 4'-chloroacetophenone. The resultant mixture was stirred with heating overnight at 100° C. The reaction mixture was poured into 2,000 ml of ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. n-Hexane was added to the residue, and the resultant crystals were collected by filtration and washed with n-hexane. Thus was obtained 224 g of 4'-phenylthioacetophenone as crystals (m.p. 48°-50° C.).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[Cl:26][C:27]([F:32])([F:31])[C:28]([O:30][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29]
Reactant: O=C(O)C(F)(F)Cl
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)Cl)CCCCC1

Procedure:
1-Nitrosocyclohexyl 2-chloro-2,2-difluoroacetate was prepared from cyclohexanone oxime, lead tetraacetate and 2-chloro-2,2-difluoroacetic acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 2.13-2.42 (3H, m), 1.79-1.99 (4H, m), 1.51-1.74 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cc([N+](=O)[O-])ccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask or vial containing 2-methoxy-4-nitro-benzaldehyde (1.0 g, 5.5 mmol), add dichloroethane (40 mL), 1-methylpiperazine (1.0 ml, 8.3 mmol), and sodium triacetoxyborohydride (3.5 g, 16.5 mmol). Stir at room temperature overnight. Quench with saturated aqueous NaHCO3 and extract with CH2Cl2 (1×) and EtOAc (2×). Combine the organic portions, dry over MgSO4, filter, and concentrate under vacuum. Purify the residue by flash chromatography on silica gel using a gradient of MeOH (0.005% NH4OH)/CH2Cl2 (5% to 10%) to give the title compound. MS (ES+) 266.0 (M+1)+. 1H NMR (CDCl3): δ 7.80 (dd, J=8 Hz, 2 Hz, 1H), 7.66 (d, J=2 Hz, 1H), 7.56 (J=8 Hz, 1H), 3.89 (s, 3H), 3.58 (s, 2H), 2.52 (br. 4H), 2.45 (br, 2H), 2.28 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:11])[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]CC.[Na+].Cl>C(O)C>[N:1]1([CH2:7][CH:8]2[CH2:11][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:19][C:9]2=[NH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C#N)CN1CCCCC1
Reactant: NNc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C1NN(c2ccccc2)CC1CN1CCCCC1

Procedure:
α-Piperidinomethylacrylonitrile (17g) and phenylhydrazine (10.8g) were added to a solution of sodium ethoxide (2.3g sodium) in ethanol (200 ml). The resulting solution was boiled under reflux for 2 hours and a solid precipitate formed during the reaction. Dilute hydrochloric acid (50 ml of 2N) was added to the reaction mixture and the solution was evaporated to dryness. The solid residue was extracted with dry ethanol and the product crystallised from the ethanol as colourless plates (melting point 186-7° C).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[S:10](Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][S:10][N:9]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(Cl)nc1N
Solvent: C1COCCO1
Product: Clc1ccc2nsnc2n1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
6-Chloropyridine-2,3-diamine (Example 23, Step 1) (150 mg, 1.045 mmol) was taken-up in dioxane (21.0 ml) under argon at room temperature. Thionyl chloride (686 μl, 9.40 mmol) was added dropwise over 15 minutes. The mixture was then stirred at 75° C. for 24 hours. The reaction was quenched with water and extracted three times with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel chromatography (0-65% ethyl acetate/hexanes) to afford 5-chloro[1,2,5]thiadiazolo[3,4-b]pyridine. LRMS (APCI) calc'd for (C5H3ClN3S) [M+H]+, 172. found 172.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH:30]2[CH2:35][CH2:34][N:33]([C:11]([CH:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:10][CH2:9]3)=[O:13])[CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)CCN1CCC(C(=O)O)CC1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)C2CCN(CCC(C)C)CC2)CC1
Reaction time: 4 h
Yield: 17.7 %

Procedure:
The preparation of Example 13: 1-(3-Methyl-butyl)-piperidine-4-carboxylic acid (0.1 g, 0.50 mmol) was dissolved in DMF (5 mL) and treated with (4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (0.175 g, 0.50 mmol), diisopropylethylamine (0.26 mL, 1.5 mmol), and HBTU (0.19 g, 0.50 mmol). The reaction was stirred for 4 hours, then diluted with EtOAc (125 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 47 mg (18%) of {4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl }-[1-(3-methyl-butyl)-piperidin-4-yl]-methanone.
Reaction SMILES: FC1C=CC=CC=1C[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14]C1C=CC=CC=1F)[CH:8]=[O:9].FC1C=C(C=CC=1)CC1C=C(C=CC=1OCC1C=CC=C(F)C=1)[CH:34]=[O:35].FC1C=CC=CC=1[CH2:54][O:55]C1C=CC(C=O)=CC=1>FC1C=C(C=CC=1)COC1C=CC(C=O)=CC=1>[CH3:34][O:35][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:55][CH3:54])[C:12]=1[O:13][CH3:14])[CH:8]=[O:9]
Reactant: O=Cc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)c(Cc2cccc(F)c2)c1
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Agent: O=Cc1ccc(OCc2cccc(F)c2)cc1
Product: COc1cc(C=O)cc(OC)c1OC

Procedure:
Calculate the percent content of 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde in the 4-(2-fluorobenzyloxy)benzaldehyde examined or of the 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde in the 4-(3-fluorobenzyloxy)benzaldehyde examined by internal standard calculation. The value of the limit of quantitation (LOQ) for (3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde and of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde is 0.005% by weight. The value of the limit of detection (LOD) for both considered impurities is 0.0025% by weight.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[Cl:10]/[CH:11]=[CH:12]\[CH2:13]Cl>>[Cl:10]/[CH:11]=[CH:12]\[CH2:13][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: Cl/C=C\CCl
Product: O=[N+]([O-])C=C1NCCN1C/C=C\Cl

Procedure:
Method B, reacting 2-(nitromethylene)imidazolidine with cis-1,3-dichloropropene. Melting point: 117° - 118° .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N:7][C:6]([NH2:13])=[CH:5]2.[Cl:14][C:15]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[C:18]([NH2:26])[N:19]=[CH:20]2.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N:7][C:6]([N:13]=[C:27]=[S:28])=[CH:5]2.[Cl:14][C:15]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[C:18]([N:26]=[C:27]=[S:28])[N:19]=[CH:20]2
Reactant: Nc1cc2cc(Cl)c(Cl)cc2cn1
Reactant: Nc1cc2c(Cl)c(Cl)ccc2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc2c(Cl)c(Cl)ccc2cn1
Product: S=C=Nc1cc2cc(Cl)c(Cl)cc2cn1
Temperature: 40 °C
Reaction time: 4 h
Yield: 40.7 %
Yield: 46.8 %

Procedure:
To 6,7-dichloroisoquinolin-3-amine and 5,6-dichloroisoquinolin-3-amine (0.410 g, 1.924 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.469 g, 2.021 mmol) and the reaction mixture was stirred at 40° C. for 4 hours. The reaction was cooled to room temperature and chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield the separated regioisomers, 6,7-dichloro-3-isothiocyanatoisoquinoline (0.2 g, 0.784 mmol, 40.7% yield) and 5,6-dichloro-3-isothiocyanatoisoquinoline (0.23 g, 0.902 mmol, 46.8% yield) as yellow solids. 5,6-dichloro-3-isothiocyanatoisoquinoline: 1H NMR (500 MHz, CDCl3) δ ppm 9.10 (s, 1H), 7.87 (d, J=8.85 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=8.55 Hz, 1H). MS (LC/MS) R.T.=3.63; [M+H]+=255.0. 6,7-dichloro-3-isothiocyanatoisoquinoline: 1H NMR (500 MHz, CDCl3) δ ppm 9.04 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.37 (s, 1H). MS (LC/MS) R.T.=3.42; [M+H]+=255.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[Mg].[B:13](OC)([O:16]C)[O:14]C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([B:13]([OH:16])[OH:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(Br)cc1F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)cc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 116.6 %

Procedure:
100 ml of a THF solution of 22.8 g (104 mmol) of 3-fluoro-4-ethoxybromobenzene was dropped, while stirring, at 40 to 60° C. to 3.03 g (124.8 mmol) of dried turnings magnesium, and refluxed under heating after dropping for one hour. The solution was cooled by a coolant to −70° C. and, a THF solution of 16 ml (132.5 mmol) of trimethyl borate (THF: 70 ml) was dropped under stirring. After stirring at −70° C. for 3 hours, and further stirring at a room temperature for 20 hours, the reaction solution was cooled to 5° C., and 50 ml of 6M hydrochloric acid was added. After separating the organic layer, the aqueous layer was extracted with 100 ml of ethyl acetate. After mixing the organic layer, it was washed with water and then with an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, concentrated under a reduced pressure, to obtain 22.3 g of crude 3-fluoro-4-ethoxyphenyl boronic acid. The obtained crude boronic acid derivative was used without purification for a second step.
Reaction SMILES: [CH:1](=[N+:8]([O-:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:17]([O:44]CCCCCCCCCCCC)([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[CH2:57](I)[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68]>>[CH2:1]([N:8]([CH:9]([P:17](=[O:44])([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:16][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH3:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCI
Reactant: CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Reactant: [O-][N+](=Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCON(Cc1ccccc1)C(c1ccccc1)P(=O)(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Temperature: 70 °C
Yield: 27.8 %

Procedure:
A mixture of 5.0 g (23 mmol) of N-benzylidenebenzylamine N-oxide, 17.6 g (30 mmol) of tri-n-dodecyl phosphite and 29.6 g (100 mmol) of n-dodecyl iodide is heated at 70° C. for 24 hours. The reaction mixture is concentrated in vacuo and the residue is purified by HPLC (4:1 hexane:ethyl acetate eluent) followed by flash chromatography (methylene chloride eluent) to give 5.1 g (28% yield) of the title compound as a white solid melting at 38°-40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1([C:33]([Cl:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:35].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:33]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:34])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCCC4)c3)c2o1

Procedure:
50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114) and 36.7 mg (0.28 mmol) of cyclopentanecarbonyl chloride are reacted together by general method F. 33.2 mg (45.1% of theory) of the title compound are obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Br:24][C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][C:26]=1[Cl:33].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:24][C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][C:26]=1[Cl:33])[CH2:31][C:14]([CH3:13])([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CCC(C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(C)(Cc1ccc(Cl)c(Br)c1)C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 5.8 ml (41.6 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 16.6 ml (41.6 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 5.06 g (32.0 mmol) of tert-butyl 2-methylbutanoate in 20 ml of THF was added, the reaction temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 10.0 g (35.2 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, and the temperature was once more kept below −60° C. The reaction mixture was then slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 7.62 g (65.9% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To a solution of 5-bromo-2-(tert-butoxycarbonyl)aminopyridine (25.0 g, 91.5 mmole) in DMF (400 mL) was added portionwise with stirring a 60% dispersion of NaH in mineral oil (4.0 g, 100 mmole). The reaction was stirred for 15 min, then methyl bromoacetate (15 mL, 158.5 mmole) was added dropwise over 15 min. After stirring for 18 h at room temperature the reaction was concentrated to dryness. The remaining residue was taken up in EtOAc (200 mL) and H2O (200 mL) and filtered to remove insoluble material. The EtOAc phase was separated, washed with brine, dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (10% EtOAc/Hexane) gave the title compound (16.56 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 7.73 (d, J=2.5 Hz, 1 H), 7.71 (d, J=2.5 Hz, 1 H), 4.69 (s, 2 H), 3.75 (s, 3 H), 1.51 (s,9H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@@H:10]1[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=O)(C)(C)C>C(OCC)(=O)C.ClCCl>[ClH:1].[ClH:1].[ClH:1].[N:28]1([C:25]2[CH:24]=[CH:23][C:22]([C@H:10]3[CH2:11][NH:12][CH2:13][CH2:14][NH:9]3)=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CCCCC3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1cc(N2CCCCC2)ccc1[C@H]1CNCCN1
Reaction time: 2 h
Yield: 98 %

Procedure:
Hydrogen chloride (4N, 1.5 ml) in ethyl acetate was added to a solution of (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (455 g, 1.02 mmol) in dichloromethane (10 ml) and the solution was stirred for 2 hours. Filtration and washing with ethyl acetate of the precipitant gave (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine trihydrochloride (353 mg, 98%) as white crystals.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.I[CH2:15][CH2:16][OH:17].[C:18]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([OH:35])[C:29]([CH3:37])([CH3:36])[CH2:28]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCCC>ClC1C=CC=CC=1>[C:18]([O-:26])(=[O:25])[CH3:19].[C:18]([O:26][CH:27]1[CH2:28][C:29]([CH3:37])([CH3:36])[N:30]([O:35][CH2:15][CH2:16][OH:17])[C:31]([CH3:33])([CH3:34])[CH2:32]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCI
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCCC
Solvent: Clc1ccccc1
Product: CC(=O)[O-]
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCCO

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-iodoethanol and 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine in chlorobenzene. The crude reaction mixtuire is passed through silica gel with heptane and then heptanelethyl acetate to afford the title compound.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:28])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)Nc2ccccc2)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (0.92 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.37 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.68 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(4-(3-phenylureido)butyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:37])C(=O)C1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][C:21]3[C:29]([Br:37])=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2Br)cc1
Temperature: 80 °C

Procedure:
A mixture of N-[4-(tert-butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide (620 mg) (Example 8) and NBS (330 mg) in benzene (50 ml) was heated at 80° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give the title compound. MS (ES+):464 (M+H)+; (ES−): 462 (M−H) Calc'd. for C23H22BrN5O—463.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1O>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:4]2[C:3]([CH2:2][O:1][C:26]3[C:25]([F:28])=[CH:24][C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:22][C:21]=3[F:20])=[C:7]([C:8]([F:11])([F:9])[F:10])[S:6][N:5]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: N#Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting from 4-[4-(hydroxymethyl)-5-(trifluoromethyl)-1,2-thiazol-3-yl]benzonitrile, following Steps 4-6, and using ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-propanoate. Upon hydrolysis, the desired compound 261 was afforded as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.98 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.88 (d, J=9.6 Hz, 2H), 5.23 (s, 2H), 2.87 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H). 19F NMR (300 MHz, CD3OD) δ: −56.54, −77.52, −129.65. Mass spectrum (ESI, m/z): Calcd. for C21H13F5N2O3S, 467.0 (M−H). found 466.9.