Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][N:18](C=O)[CH3:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH2:17][NH:18][CH3:19])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1csc2ccc(F)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNCc1sc2ccc(F)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 5-fluoro-3-methyl-benzo[b]thiophene (4.83 g, 29.1 mmol) in THF (50 mL) at −30° C. under N2 was added n-butyllithium (20.0 mL of a 1.6 M solution in hexanes, 32.0 mmol) dropwise. The resulting orange solution was stirred for 1 h and then DMF (3.4 mL, 43.7 mmol) was added in one portion. The solution was warmed slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (5.55 g, 97%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.80 (dd, J=9.0, 4.8 Hz, 1H), 7.53 (d J=9.3, 2.6 Hz, 1H), 7.31-7.24 (m, 1H), 2.76 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][C:11]3[C:12]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[O:37])=[CH:34][N:33]=[CH:32]1.[Li]CCCC>>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][C:11]3[C:12]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:39]=[N:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=3)[OH:37])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Product: CCN(CC)c1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-N,N-diethylquinolin-2-amine (380 mg, 0.809 mmol, Intermediate 46) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (206 mg, 0.809 mmol, Intermediate 36, step c) and was evacuated and re-filled with argon. THF (13.5 mL) was added, and the solution was cooled in a dry ice acetone bath for 10 minutes. n-BuLi (1.6 M in hexane, 0.506 mL, 0.809 mmol), was added dropwise by syringe. The mixture was stirred at −78° C. for 30 minutes, then in an ice water bath for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 50-100% EtOAc-heptanes) to provide the title compound as a white foam.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.OO.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:31])[CH2:22][N:23]2[CH2:28][CH:27]([CH3:29])[O:26][CH:25]([CH3:30])[CH2:24]2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>[OH-].[K+]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH3:31])[CH2:22][N+:23]2([O-:3])[CH2:24][CH:25]([CH3:30])[O:26][CH:27]([CH3:29])[CH2:28]2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(Cc1ccc(C(C)(C)C)cc1)CN1CC(C)OC(C)C1
Agent: OO
Agent: [K+]
Agent: [OH-]
Product: CC(Cc1ccc(C(C)(C)C)cc1)C[N+]1([O-])CC(C)OC(C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 120 ml of acetic anhydride and 120 ml of 30% hydrogen peroxide is added dropwise to 40 g of 4-[3-(p-tert.-butyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine while cooling with an ice-bath so that the temperature does not exceed 45°-50° C. After stirring at room temperature for 16 hours, the mixture is cooled to -10° C. and treated with 280 ml of 40% potassium hydroxide solution, exhaustively extracted with chloroform and concentrated in vacuo at 30° C. (bath temperature). The residue is stirred at room temperature with 2-N sodium hydroxide solution for 16 hours and again extracted several times with chloroform. The combined chloroform extracts are washed neutral with sodium chloride solution, dried over sodium sulphate and evaporated. The highly viscous, syrupy residue is crystallised from ether/pentane. There is obtained pure 4-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine-4-oxide in the form of the hydrate; melting point 115°-118° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64](OC2C=CC([N+]([O-])=O)=CC=2)=[O:65])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[C:76]([O:80][C:81]([NH:83][CH2:84][CH2:85][OH:86])=[O:82])([CH3:79])([CH3:78])[CH3:77].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64]([O:86][CH2:85][CH2:84][NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:82])=[O:65])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)Oc4ccc([N+](=O)[O-])cc4)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)OCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of the compound of Example 5A (83 mg, 0.081 mmol), 2-(tert-butyloxycarbonylamino)ethanol (26 mg, 0.161 mmol), DMAP (10 mg) and Hunig's base (0.1 mL) in acetonitrile (1 mL) was stirred at 90° C. overnight. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (73 mg, 86% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[O:7][C:6]=2[CH:16]=1.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)C1CNc2ccc(C)cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)OC(C(=O)O)CN2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To the suspension of ethyl 7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (8.5 g, 38.5 mmol) in water (60 mL) was added NaOH (3.8 g, 96.1 mmol). The suspension was stirred at 100° C. for 30 min under N2 atmosphere. The reaction was cooled to room temperature and acidified to pH 2 with conc. HCl. The resulting precipitate was filtered, washed with water and dried to obtain 7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (5.1 g, 68.7%). 1H NMR (400 MHz, DMSO-d6) δ 6.51 (s, 1H), 6.46-6.41 (m, 2H), 5.60 (br s, 1H), 4.73 (t, J=3.6 Hz, 1H), 3.33-3.31 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][C:18]1[CH:23]=[C:22]([C:24]([NH:16][CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[CH:2][NH:1][C:6]4=[N:7][CH:8]=[CH:9][C:5]=34)[CH2:15][CH2:14]2)=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 2-methyl-4-pyridinecarboxylic acid (63.1 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E12 (72 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.55 (2H, m), 8.17 (1H, s), 7.62 (1H, s), 7.53 (1H, d), 7.18 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.35 (3H, s), 3.25 (2H, dt), 1.90 (2H, m), 1.53 (2H, m), MS(ES+) 337 [M+H]+.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:34]([O:41][CH:42]1[CH:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:46]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:45]([CH2:64][O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:44][C:43]1=[O:73])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[CH2:34]([O:41][C@@H:42]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:44][C:43]1([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1)[OH:73])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Fc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cc(Cc3cc4cc(F)ccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 0.97 ml, 1.55 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-yl-methyl)-5-fluorobenzo[b]thiophene (520 mg, 1.41 mmol) in THF (15 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 10 minutes. To this solution, a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyl-tetrahydropyran-2-one (835 mg, 1.55 mmol) in THF (3 ml) was added dropwise. The mixture was stirred at −78° C. for one hour, and a saturated ammonium chloride aqueous solution was added thereto to stop the reaction. The reaction mixture was extracted with ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (770 mg, 66%).
Reaction SMILES: [OH:1][NH:2][C:3]([C@H:5]1[CH2:12][C:9]2([CH2:11][CH2:10]2)[CH2:8][NH:7][C@@H:6]1[C:13]([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=[O:4].[O-]S([O-])(=O)=O.[Ba+2]>CO>[OH:1][NH:2][C:3]([C@H:5]1[CH2:12][C:9]2([CH2:10][CH2:11]2)[CH2:8][NH:7][C@@H:6]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=[O:4]
Reactant: CC(C)c1cccc(C2=CCN(C(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)NO)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)c1cccc(C2CCN(C(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)NO)CC2)c1

Procedure:
(6S,7S)—N-hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide (10 mg) was hydrogenated at 1.0 atm over BaSO4 in MeOH for one hour to give the desired product, Ms(ESI): (M+H)+=400.4.
Reaction SMILES: C([O:4][CH:5]1[C:13]2[N:12]=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[Cl:14][C:10]1[CH:11]=[N:12][C:13]2[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=2[CH:9]=1
Reactant: CC(=O)OC1CCc2cc(Cl)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC1CCc2cc(Cl)cnc21
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-6,7-dihydro-5H-cyclopentapyridin-7-yl acetate (1.57 g, 7.42 mmole) in MeOH (36 ml) was added aqueous NaOH solution (1M, 8.9 ml, 8.9 mmole) and the mixture was stirred at 22° C. for 1.5 h. The mixture was diluted with water and extracted with dichloromethane, the organic layer was dried and evaporated to give the title compound as a dark red liquid which crystallized on standing. MS (ESI): m/z=170.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:6]2([NH:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=[CH:2][NH:7]2)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: Clc1nccc(NCc2cccs2)n1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CC(C)c1ccc(C2(NCc3cccs3)C=CN=CN2)cc1

Procedure:
[2-(4-Isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amine (142 mg) was obtained by following general procedure Q1 from (2-chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl-amine (130 mg, 0.58 mmol) and 4-isopropylphenylboronic acid (140 mg, 0.86 mmol). LCMS m/z: 311 (M+1)+. [4-(4-Isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amine was obtained by following general procedure Q1 from (4-Chloro-pyrimidin-2-yl)-thiophen-2-ylmethyl-amine and 4-isopropylphenylboronic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:32][CH2:31]1)=[O:10])(=[O:3])[CH3:2]
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1

Procedure:
Starting materials: (a) 3-acetylaminobenzoic acid is converted by means of thionyl chloride into the acid chloride [m.p. 101°-102°], and the latter is then condensed with 1-[2-(4-chlorophenyl)ethyl]piperazine, yielding 1-(3-acetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine in the form of a foam. The latter is reacted with (BOC)2O to form 1-{3-[(N-acetyl-N-tert-butyloxycarbonyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 113°-114°. The subsequent cleavage with dimethylaminoethylamine results in a foam, which corresponds to 1-[3-(N-tert-butyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][N:16]([C:18](C3C=C4C(=CC=3)NCCC4)=[O:19])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7].[C:30]([N:33]1[C:42]2[C:37](=[CH:38][C:39]([Br:43])=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]1C(N1CC(N2CCNCC2)C1)=O)(=[O:32])[CH3:31].N1(C2CN(C(C3C=C4C(=CC=3)NCCC4)=O)C2)CCNCC1>>[C:30]([N:33]1[C:42]2[C:37](=[CH:38][C:39]([Br:43])=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]1[C:18]([N:16]1[CH2:17][CH:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:7])[CH2:9][CH2:10]2)[CH2:15]1)=[O:19])(=[O:32])[CH3:31]
Reactant: O=C(c1ccc2c(c1)CCCN2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reactant: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)N1CC(N2CCNCC2)C1
Agent: O=C(c1ccc2c(c1)CCCN2)N1CC(N2CCNCC2)C1
Product: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1

Procedure:
The title compound was prepared in an analogous manner to that of compound 357 substituting compound 25e for compound 20c. LC/MS m/z (M+H+) 532.0, (M+2H+) 534.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([C:52]1[S:60][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:54]=2[CH:53]=1)=[O:51]>CN(C=O)C>[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([C:52]1[S:60][C:55]2[CH2:56][N:57]([C:8](=[O:10])[CH2:7][O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:58][CH2:59][C:54]=2[CH:53]=1)=[O:51]
Reactant: COc1cccc(OCC(=O)O)c1
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cccc(OCC(=O)N2CCc3cc(C(=O)Nc4ccccc4N)sc3C2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of (3-Methoxy-phenoxy)-acetic acid (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (1.0 eq) obtained in step VII of example 216 was then added and mixture was stirred at room temperature overnight.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[OH-].[Na+].S(OC)(O[CH3:15])(=O)=O>COCCOC>[CH3:1][N:2]([CH3:15])[C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: CNC1=CC(=O)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CN(C)C1=CC(=O)OC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 54.1 %

Procedure:
2 g (0.18 mol) of 4-(methylamino)furan-2(5H)-one are introduced in 20 ml of 1,2-dimethoxyethane, and 0.72 g of sodium hydroxide is added. 2.2 g of dimethyl sulphate in 5 ml of 1,2-dimethoxyethane are metered into the suspension and stirred at 40° C. for 5 h. The solvent is removed in vacuo and 50 ml of water are added to the residue. This mixture is then extracted with 50 ml of dichloromethane. The organic phase is dried over sodium sulphate and then evaporated down in vacuo. 1.2 g of 4-(dimethylamino)furan-2(5H)-one are obtained as a solid with a purity of 96% (yield 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:40]4[N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:43]=[CH:42][CH:41]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2)CC1
Yield: 56 %

Procedure:
4-[3-Formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester is reacted with 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid as described in Example 66 to afford 4-{1-[4-(tert-butoxylcarbonyl-1H-pyrrol-2-yl)-phenyl]-3-formyl-1H-indol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester as a beige solid (56% yield). ESI/MS 571 (M+1), 515 [M-C(CH3)3]; NMR (CDCl3) 10.28 (1H, s); 8.27 (1H, d, J=6 Hz); 7.59 (2H, d); 7.41 (6H, m); 6.32 (2H, m); 3.36 (8H, m); 1.46 (9H, s); 1.44 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)[C:21]([O:38][CH3:39])=[N:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:39][O:38][C:21]1[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][N:20]=1
Reactant: COc1ncc(Br)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ncc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 110 °C
Yield: 56.9 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (80 mg; 0.38 mmol), tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-pyrazin-2-yl)-3-piperidyl]carbamate (181 mg, 0.4550 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), xantphos (45 mg, 0.076 mmol), and sodium tert-butoxide (75 mg, 0.76 mmol) in toluene 3.0 mL was stirred at 110° C. 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 75% EtOAc) to give the desired product 112 mg 57% yield. MS (ESI) m/z: 518.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[CH:69]=[C:68]([CH2:70][C:71](O)=[O:72])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:71](=[O:72])[CH2:70][C:68]5[O:67][N:66]=[C:65]([CH3:64])[CH:69]=5)[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)Cc2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.1 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-5-isoxazoleacetic Acid (0.135 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.269 g). 1H NMR Spectrum: (DMSO d6 373K) 1.79 (m, 2H), 1.98 (m, 2H), 2.23 (s, 3H), 3.50 (m, 2H), 3.79 (m, 2H), 3.92 (s, 2H), 3.97 (s, 3H), 4.77 (m, 1H), 6.18 (s, 1H), 7.24 (m, 2H), 7.42 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 526.