Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: CCOC(=O)C1CCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-ethyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidine-4-carboxylate (Example 31, 9.2 mg, 0.018 mmol) was dissolved in a mixture solvent of THF:MeOH:water (2:2:1 v/v; 0.2 mL), followed by addition of lithium hydroxide monohydrate (2.3 mg, 0.055 mmol). After stirring at ambient temperature overnight, the reaction was diluted with water (1 mL), acidified with 10% citric acid, and extracted with EtOAc (3×1 mL). The combined organic layers were concentrated, and the crude material was purified by reverse-phase column chromatography, eluting with 5 to 55% MeOH/water to yield the final product as a solid. MS (apci) m/z=471.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([N:12]=[N+]=[N-])[CH3:11])[CH:5]=1.[H][H]>C(O)C.[C].[Pd]>[NH2:12][CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:15])[CH3:11]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(C(C)N=[N+]=[N-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(C(C)N)c1
Yield: 57.3 %

Procedure:
600 mg of the methyl 3-(1-azidoethyl)benzoate [100-1] was dissolved in 15 mL of ethanol, 200 mg of 10% palladiumcarbon catalyst was added thereto, and stirred overnight in a hydrogen atmosphere. The insolubles were filtered through celite, washed with ethanol, and then the filtrate was concentrated under reduced pressure to obtain 300 mg of methyl 3-(1-aminoethyl)benzoate [100-2] as a colorless oily product.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][NH2:26])[CH2:18][CH2:17]1.C(O)(=O)/C=C/C([O-])=O>>[O:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][N:26]=[C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:20][CH2:21]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: NOCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: C1CCCCCC(=NOCCCN2CCOCC2)CCCCC1

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 25.64 g. (0.11 moles) of morpholinopropoxyamine dihydrochloride the title compound is prepared as in Example 13. Yield: 28.4 g. (87%). Hydrogen fumarate, m.p.: 118°-120° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:21]=[O:22].CCN(C(C)C)C(C)C>C1COCC1>[CH2:23]([NH:20][C:21]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (62 mg, 0.24 mmol, 1.0 eq) and (isocyanatomethyl)benzene (35 mg, 0.26 mmol, 1.1 eq) in THF (2 mL) were added DIPEA (93 mg, 0.72 mmol, 3.0 eq). The mixture was stirred at rt for 3 h and the solvent was removed in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% NH3.H2O) to give the title compound as a light brown solid (23 mg, yield: 11%). 1H NMR (400 MHz, CD3OD) δ: 8.32 (s, 1H), 7.15-7.09 (m, 6H), 6.91 (d, J=3.6 Hz, 1H), 4.23-4.20 (m, 3H), 3.87-3.83 (m, 1H), 3.46-3.34 (m, 3H), 2.09-2.05 (m, 1H), 1.81-1.80 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 393.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH2:30][NH2:31])[CH3:27]>>[CH2:26]([NH:28][CH2:29][CH2:30][NH:31][C:20]([C:14]1[C:15](=[O:19])[NH:16][C:17]2[C:12]([C:13]=1[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:21])[CH3:27]
Reactant: CCNCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CCNCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-ethylethylenediamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, br s), 10.68 (1H, br s), 8.17 (1H, s), 7.27 (3H, br s), 7.12 (2H, t, J=8.7 Hz), 4.00 (2H, s), 2.62-2.48 (6H, m), 0.99 (3H, t,J =7.1 Hz); HRMS calcd for C20H21FN4O3+H+: 385.1676. Found 385.1685.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[N:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(I)cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(I)cnc3n2)cc1
Temperature: 110 °C
Yield: 73 %

Procedure:
646 mg (corresponding to 3.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 668 mg (corresponding to 3.0 mmol) of 2-amino-5-iodopyrimidine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 8 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 15 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 3 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 737 mg (corresponding to 2.19 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyrimidine (FIG. 1-8, Step 2).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 98445.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 24.0 g, 0.48 mol) was added portionwise to a stirred solution of anhydrous benzyl alcohol (64.5 g, 0.60 mol) in THF (1.0 L). After the mixture was stirred for 1 h, a solution of 1-bromo-3,5-difluorobenzene (76.8 g, 0.40 mmol) in THF (100 mL) was added dropwise over a period of 1 h. The reaction was stirred at room temperature for 2 d. Water (400 mL) was added and the THF was removed in vacuo. The aqueous layer was extracted with hexane (3× 150 mL). The combined organic extracts were washed with 2N NaOH (2× 100 mL) then, dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (110.7 g, 98%) as a light yellow oil that was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][O:22][C:23]3[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=3)[CH2:18][CH2:19][C:13]=2[C:12]([O:34][CH3:35])=[C:11]([O:36][CH3:37])[C:10]=1[O:38][CH3:39].Cl>C(OCC)C.C1COCC1.O>[CH3:35][O:34][C:12]1[C:13]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[CH:32][CH:33]=3)[CH2:16][CH2:15][C:14]=2[C:9]([O:8][CH3:7])=[C:10]([O:38][CH3:39])[C:11]=1[O:36][CH3:37]
Reactant: CCOC(=O)c1ccc(OCCC2CCc3c(c(OC)c(OC)c(OC)c3OC)CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(CO)cc1)CC2
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
To a suspension of lithium aluminum hydride (91.8 mg) in diethyl ether (10 ml) was dropwise added a solution of ethyl 4-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]benzoate (553 mg) in THF (10 ml) with cooling with ice. After stirring was continued for 15 min, 10% hydrochloric acid was added to the reaction mixture, which was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from hexane-ethyl acetate to yield the entitled compound (320 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[C@H:10]([CH3:24])[N:9]=1>O1CCCC1.CO.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[C@H:10]([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O

Procedure:
A solution of 68.2 g (0.198 mol) of (S)-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one in a mixture of 400 ml of tetrahydrofuran and 950 ml of methanol is treated with Raney-nickel which has previously been washed several times with methanol and tetrahydrofuran and the suspension is hydrogenated while stirring and cooling with water, whereupon it is filtered and the filtrate is evaporated. The residue is recrystallized from ether, there being obtained (S)-7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 221°; [α]25D =-13.8° (1 percent solution in methylene chloride).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[CH3:30][N:25]([CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCN(C)S(C)(=O)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCN(C)S(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=1, m/z=522.1; 1H NMR (CDCl3) 1.23 (m, 1H), 1.48 (d, 3H), 1.68-1.99 (m, 3H), 2.11-2.31 (m, 3H), 2.56 (s, 3H), 2.66 (s, 3H), 2.68 (s, 3H), 2.84-3.08 (m, 3H), 5.68 (m, 1H), 6.92 (d, 1H), 7.15 (d, 1H), 7.25 (m, 4H), 7.31 (m, 4H), 8.43 (d, 1H).
Reaction SMILES: O[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:15]O)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.CCOC(C)=O.[H][H]>[Pd].CC(O)=O>[CH3:15][C:10]1[C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc2c1-c1ccccc1C2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc2c1-c1ccccc1C2
Yield: 77.3 %

Procedure:
A solution of 9-hydroxyfluoren-4-methanol (2.6 g, 12.2 mmol) in 1.1 EtOAc:AcOH was charged with catalytic amount of 10% palladium on charcoal. The mixture was treated with hydrogen under 1600 psi, at room temperature for three days. The catalyst was removed and the solvent was evaporated under reduced pressure. Recrystalyzation from MeOH afforded 1.7 g (77.0%) of the product as a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
An autoclave was charged with 3.9 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine, 3 ml of ethanol and 156 mg of moist 5% palladium-carbon (water content 52% by weight), hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed. Five hours after the start of hydrogen introduction, no hydrogen absorption was observed any more, so that the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, and the filtrate obtained was analyzed by high performance liquid chromatography. (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine was obtained in a yield of 36 mole percent.
Reaction SMILES: CNCCN1CCOCC1.FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(C2C=C(C=CC=2)C(O)=O)=O)C=1)=O.[CH2:55]([N:57]([CH2:101][CH2:102][N:103]1[CH2:108][CH2:107][O:106][CH2:105][CH2:104]1)[C:58](=[O:100])[C:59]1[CH:99]=[CH:98][CH:97]=[C:61]([C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([N:71]3[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]3)=[CH:67][C:66]=2[C:77]2[CH:82]=[C:81]([C:83](=[O:96])[NH:84][CH2:85][C:86]3[CH:91]=[CH:90][CH:89]=[C:88]([C:92]([F:95])([F:94])[F:93])[CH:87]=3)[CH:80]=[CH:79][N:78]=2)=[O:63])[CH:60]=1)C>>[CH3:55][N:57]([CH2:101][CH2:102][N:103]1[CH2:108][CH2:107][O:106][CH2:105][CH2:104]1)[C:58](=[O:100])[C:59]1[CH:99]=[CH:98][CH:97]=[C:61]([C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([N:71]3[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]3)=[CH:67][C:66]=2[C:77]2[CH:82]=[C:81]([C:83](=[O:96])[NH:84][CH2:85][C:86]3[CH:91]=[CH:90][CH:89]=[C:88]([C:92]([F:94])([F:95])[F:93])[CH:87]=3)[CH:80]=[CH:79][N:78]=2)=[O:63])[CH:60]=1
Reactant: CCN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CNCCN1CCOCC1
Agent: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared by coupling N-methyl-2-morpholinoethylamine to 3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzoic acid 4.1e, using the procedure described for the preparation of N1-ethyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)-carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8. MS (ES, m/z): 743 [M+H]+
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccc(F)cc1
Product: NC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.42 mmol) and (S)-2-amino-2-(4-fluoro-phenyl)-acetamide (119.2 mg, 0.64 mmol) as starting materials, and isolated (10 mg, 6.3%) as white solid; LC-MS (UV peak area, ESI) 95.12%, 384.8 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>CN(C=O)C.ClC1C=CC=CC=1>[Cl:16][C:9]([C:8]1[CH:12]=[CH:13][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 4-acetoxybenzoic acid (200 mg, 1.11 mmol), thionyl chloride(1.6 mL), 1 drop of DMF, and 7.5 mL of chlorobenzene was heated to 80° C. for 1.5 hrs. The reaction was then cooled to room temperature and the solvent and excess thionyl chloride were removed in vacuo. Theoretical yield of the title compound was assumed and the residue was used as is.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[O:12]1CCC[CH2:13]1>B>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][NH2:11])=[C:2]([O:12][CH3:13])[CH:7]=1
Reactant: C1CCOC1
Reactant: N#CCc1ccc(Cl)cc1Br
Agent: B
Product: COc1cc(Cl)ccc1CCN

Procedure:
A portion of 2-(2-bromo-4-chlorophenyl)acetonitrile (7.1 g; 39.1 mmol) was directly dissolved in borane solution (78.2 mL of a 1.0 M solution in tetrahydrofuran; 78.2 mmol), and the resulting solution was stirred and heated to reflux. After refluxing for a total of 90 minutes, the heat was removed and the solution was allowed to cool for a few minutes, and then 16 mL of methanol was carefully added to quench the solution. The resulting solution was again heated to reflux for 30 minutes. The solvent was then evaporated, and the residue was partitioned between 200 mL of 1M HCl (aq.) and 200 mL ether. The aqueous layer was filtered to remove a small amount of suspended insoluble material, and the pH of the filtrate was adjusted to pH>12 by the addition of 42% NaOH (aq.). The filtrate was then extracted with 200 mL dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 3.89 g of 2-(4-chloro-2-methoxyphenyl)ethanamine as a colorless liquid. MS (apci, pos) m/z=186.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:75]5[CH2:76][CH2:77][N:72]([CH3:71])[CH2:73][CH2:74]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CN1CCNCC1
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: CN1CCCC1=O
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 54.4 %

Procedure:
To a stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with 1-methylpiperazine (132 μL, 1.188 mmol) to give 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea as a white solid (95 mg, 54% yield); MS (ESI) m/z=588.4.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH:39]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[CH:5][CH:4]=1)(=[O:39])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide (0.1 g, 0.18 mmol) prepared in Example 187 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.3 g, 2.6 mmol), then aqueous solution (1N) of NaOH (0.9 mL, 0.9 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-carbamoyl-thiophen-2-yl)-amide as a white solid (Yield 40 mg, 39%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][OH:15])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=NO)C(C)C)cc1
Reaction time: 4 h

Procedure:
3.2 g of 5A, 7.4 g of hydroxylamine hydrochloride, 40 ml of ethanol and 80 ml of water were mixed. 4.4 g of sodium hydroxide was added to the stirred mixture at room temperature. The mixture was stirred for 4 hours at reflux temperature, cooled, poured into cold dilute hydrochloric acid and extracted with methylene chloride. The extract was dried (MgSO4) and stripped of solvent and the product was chromatographed (silica gel, methylene chloride/ether) to give 1-(4-methylphenyl)-2-methyl-1-propanone oxime (5B), as a liquid, boiling point not determined.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C(OC(=O)C)(=O)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:8]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)c1c[nH]c2ccccc12
Temperature: 50 °C
Yield: 85 %

Procedure:
In a flask, cyanoacetic acid (5.0 g, 58.8 mmol, 1.2 eq) was dissolved in acetic anhydride (50 mL) and heated at 50° C. Indole (5.8 g, 50.0 mmol, 1.0 eq) was added and the reaction was heated at 80° C. for 5 min. A white precipitate crushed out of the solution; the reaction was cooled to room temperature and then filtered. The solid obtained (620.0 mg, 85% yield) was used for the next step without further purification.