Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[O:31]=[C:30]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: C1CCNC1
Product: O=C(COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)N1CCCC1
Yield: 81.4 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (180 mg, 0.41 mmol) was reacted with pyrrolidine (0.205 ml, 2.45 mmol) to give the title compound as a light brown solid (160 mg, 82%), except that the reaction was run at 45° C. for 18 hours in the presence of 3 Å molecular sieve. NMR Spectrum 1.83 (m, 2H), 1.95 (m, 2H), 3.45 (t, 2H), 3.50 (t, 2H), 5.09 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.18 (d, 1H), 7.29 (m, 1H), 7.37 (d, 1H), 7.77-7.69 (m, 3H), 7.91 (m, 1H), 8.15 (s, 1H), 8.53 (s, 2H), 8.57 (s, 1H), 11.16 (br s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>C1COCC1>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[C:7]2[CH2:8][NH:9][C:30](=[O:31])[NH:1][C:2]=2[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2CN)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc3c2CNC(=O)N3)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a cold (0° C.) solution of tert-butyl 3-[2-amino-3-(aminomethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.020 g, 0.050 mmol) in THF (2.0 mL) under an argon atmosphere was added 1,1′-carbonyldiimidazole (0.009 g, 0.055 mmol). After stirred for 15 min, the mixture was quenched with saturated sodium bicarbonate solution. The resulting mixture was partitioned between ethyl acetate and saturated ammonium chloride solution. The separated organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.0 mL). The mixture was heated at 60° C. for 1 hr and allowed to cool to room temperature. The resulting precipitates were collected by filtration, washed with ethyl acetate and dried under reduced pressure to give tert-Butyl 3-[7-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]-1-piperidinecarboxylate. (0.007 g, yield; 33%)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28](F)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:22]2=[O:42])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:22]2=[O:42])=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)cc32)cc1
Yield: 91 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.125 mL, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example C-1, 0.20 g. 0.5 mmol) provided 0.21 g of the title compound as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH:8]1[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH:8]1[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: CN1CCN(C)C(CCO)C1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C)C(CCCl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.5 mL) was added dropwise to an ice cooled methylene chloride (5 mL) solution of 3-(2-hydroxyethyl)-1,4-dimethyl-2-piperazinone (0.40 g, described in Example 1). The reaction mixture was stirred for 30 min and poured on an ice solution of 10% sodium bicarbonate. The mixture was extracted with methylene chloride, and the organic extract was dried and evaporated to give the title compound: IR (CHCl3) 1635 cm-1 ; and NMR (CDCl3) δ 2.35 (s, 3H) and 2.90 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:10]=2[NH:9][C:8]1=[O:23].Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:10]=2[N:9]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[C:8]1=[O:23]
Reactant: COc1ccc(COn2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)c(OC)c1
Reactant: BrCC1CCCO1
Product: O=c1c2sc(-c3ccccc3)cc2n(CC2CCCO2)c(=O)n1O

Procedure:
3-(2,4-dimethoxy-benzyloxy)-6-phenyl-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) was alkylated with 2-bromomethyl-tetrahydro-furan via general procedure B1. This crude intermediate was deprotected via general procedure D1 to give the title compound which was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 7.80 (d, 2H, J=8.1 Hz), 7.78 (s, 1H), 7.52-7.44 (m, 3H), 4.23-4.06 (m, 3H), 3.74 (dd, 1H, J=7.8, 13.8 Hz), 3.59 (dd, 1H, J=7.5, 13.8 Hz), 2.05-1.58 (m, 4H); Electrospray MS: 345 (M+H); retention time: 2.43 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>>[C:13]1([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Reactant: NC(=O)C1CCNCC1
Product: NC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
Reaction of 4-chloro-6-fluoro-2-phenylquinoline and isonipecotamide in a manner similar to that of Example 4(c) gave the named compound as off-white prisms, mp 230°-233°, after recrystallization from ethanol.
Reaction SMILES: [C:1]([C:5]1([C:28]([NH2:30])=[O:29])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:3])[CH3:2]>Br.C(O)(=O)C>[C:1]([C:5]1([C:28]([NH2:30])=[O:29])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1(C(N)=O)c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Yield: 77.5 %

Procedure:
1.62 g of tert.butyl 2-benzyloxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide were dissolved in 10 ml of a 45% solution of hydrogen bromide in acetic acid. After 30 minutes the solution was evaporated and the residue was taken up in water. After filtration the filtrate was washed three times with diethyl ether and then neutralized by the addition of saturated aqueous sodium bicarbonate solution. The product was extracted from the now turbid aqueous layer with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to give 0.84 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide as a white crystalline solid of melting point 144° C.
Reaction SMILES: [CH3:1][NH2:2].C([O:5][C:6](=O)[CH2:7][C:8]1[N:9]=[CH:10][C:11]2[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)C>C(O)C>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:18]=[C:8]([CH2:7][C:6]([NH:2][CH3:1])=[O:5])[N:9]=[CH:10][C:11]=3[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]=2[CH:22]=1
Reactant: CN
Reactant: CCOC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Solvent: CCO
Product: CNC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 18 h

Procedure:
Methylamine was bubbled into a solution of 2.6 g (6.34 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-acetic acid ethylester in 60 ml of ethanol for 10 min. After standing for 18 hr, the reaction was evaporated and the residue was partitioned between 75 ml of dichloromethane and 50 ml of water. The organic layer was dried and evaporated. The residue was crystallized and then recrystallized from dichloromethane/ether to give white rods, mp 175°-177° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:18]1[CH:19]=[C:20]([F:21])[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: C#CCCc1nc2cc(F)cc(F)c2o1
Reactant: Brc1ccccn1
Product: Fc1cc(F)c2oc(CCC#Cc3ccccn3)nc2c1
Yield: 20.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (236 mg, 1.49 mmol) and 2-(but-3-ynyl)-5,7-difluoro benzo[d]oxazole (309 mg, 1.49 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 86 mg (0.3 mmol, 20%) of 5,7-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid (M.P.: 93.5-94° C.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:30][CH:29]3[NH:31][CH:26]([CH2:27][CH2:28]3)[CH:25]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH:32]1([N:31]2[CH:29]3[CH2:28][CH2:27][CH:26]2[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)[CH2:30]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(C2=CC3CCC(C2)N3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(C2=CC3CCC(C2)N3C2CCCCC2)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
Sodium triacetoxyborohydride (460 mg, 2.17 mmol, 2.0 eq.) was added to a solution of 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene (250 mg; 1.1 mmol; 1.0 eq.) and cyclohexanone (168 μl; 1.63 mmol; 1.5 eq.) in DCE (10.00 mL) and the reaction mixture was heated at 500 under nitrogen atmosphere. After 1 h, the reaction mixture was poured into a saturated solution of NaHCO3. Aqueous phase was extracted twice with DCM and combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) to give the title compound as a beige solid (220 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=8.9 Hz, 2H), 7.68 (d, J=8.9 Hz, 2H), 6.68 (d, J=5.4 Hz, 1H), 3.79-3.68 (m, 2H), 2.80-2.75 (m, 1H), 2.31 (m, 1H), 2.07-1.66 (m, 8H), 1.52 (m, 2H), 1.23-1.09 (m, 5H). HPLC (max plot) 100.0%; Rt %3.01 min. UPLC/MS: (MS+) 313.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[N:3]=1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[Cl:1][C:2]1[C:7]([N+:25]([O-:27])=[O:26])=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[N:3]=1
Reactant: CCOc1cccc(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
157.6 g (1 mole) of 2-chloro-6-ethoxy-pyridine were slowly added over 45 minutes with stirring to a mixture of 190 ml of concentrated sulfuric acid, 190 ml of 24% oleum and 100 ml of 97% nitric acid while keeping the reaction temperature between 20° and 40° C. with cooling and the mixture was allowed to stand for 5 hours while the temperature returned to room temperature. The mixture was cooled to 0° C. and filtered with a glass frit filter. The solid product was suspended in a mixture of 100 g of potassium carbonate and 250 ml of water and the suspension was stirred for 3 hours at 30° C. and was vacuum filtered. The product was washed with water and dried at 40° C. to obtain 192 g (93% yield) of 2-chloro-3-nitro-6-ethoxy-pyridine with a purity of 98%.
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13](C)[C:14](=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1>CC(O)=O>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH3:14])[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Reactant: NCC(=O)O
Agent: N#N
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (38 g, 0.506 mol) was added to crude B1 (107 g, 0.506 mol) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 7 h. Solvent was evaporated under suction with heating (50-60° C.). To the thick syrupy crude product was added 1 L of EtOAc followed by the slow addition of aqueous NaHCO3 (saturated) to adjust the pH to ˜7. Then 10 mL of 2 M NaOH was added to adjust the pH to ˜9-10. The mixture gave a solid along with organic and aqueous layers. The solid was filtered to give product containing some impurity. The solid was partitioned between 400 mL dichloromethane (DCM) and 200 mL NaHCO3, and the resultant slurry was stirred for 20 min, then filtered to remove an insoluble impurity. The DCM layer was separated and washed with 3% NaHCO3 and then brine (200 mL). The DCM layer was dried (MgSO4), filtered and concentrated to give 50 g of pure product. EtOAc layer was concentrated to give 67 g of solid product with some impurity. The aqueous layer was extracted with EtOAc (2×400 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give an additional 6.7 g of crude product. Total of 123.4 g of product was obtained, 50 g of which was very clean (yield quantitative). 1H NMR (300 MHz, CDCl3) δ 3.2 (s, 3H), 3.5 (m, 1H), 3.8 (m, 1H), 7.35 (d, 1H), 7.6 (m, 2H), 8.8 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[N:6]=1.[C:27](Cl)([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:28]>O1CCCC1.N1C=CC=CC=1>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:28])[S:3][CH:4]=2)[CH2:9][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Yield: 30.5 %

Procedure:
To a solution of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole (1.8 g) in tetrahydrofuran (5 ml) and pyridine (10 ml) was added dropwise ethoxalyl chloride (1.1 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour. After concentration of the reaction mixture, the residue was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was chromatographed on silica gel using ethyl acetate as an eluent. The eluates containing the desired compound were collected and evaporated, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain pale yellow crystals (0.7 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-ethoxalylaminothiazole, mp 125°-128° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH:27]=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH2:27][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Reactant: C1COCCN1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(CN2CCOCC2)co1)NOCc1ccccc1
Yield: 61.5 %

Procedure:
Method and purification as for preparation 157 using (3R)-N-(benzyloxy)-6-cyclohexyl-3-(4-formyl-1,3-oxazol-2-yl)hexanamide (preparation 156) (180 mg, 0.45 mmol) and morpholine (40 μl, 0.45 mmol) as starting materials to afford the title compound as a colourless oil (130 mg, 62%).
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:21][O:22][CH2:23]CN.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:2]([CH2:20][CH2:21][O:22][CH3:23])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: COCCN
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Temperature: 90 °C
Yield: 63.3 %

Procedure:
(Z)-Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (0.428 g, 1.09 mmol, Intermediate 24) and 2-methoxyethanamine (0.082 g, 1.09 mmol, Acros) were combined in DMF (3.0 mL). Potassium carbonate (0.151 g, 1.09 mmol, Fisher) was added and the reaction was heated in the microwave at 90° C. for 30 min After 30 minutes, LC/MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into water. The resulting precipitate was filtered, washed with water and dried overnight to yield a white solid (0.277 g).
Reaction SMILES: [NH2:1][NH2:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6](F)[CH:5]=1>>[Br:3][C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[N:1][NH:2]2)=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NN
Product: Brc1ccc2cn[nH]c2c1
Temperature: 125 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a 100 mL round-bottomed flask was added hydrazine (30 mL, 832 mmol) and 4-bromo-2-fluorobenzaldehyde (4.69 g, 23 mmol). The solution was stirred at 125° C. for 3 hours. After cooling to ambient temperature, the solution was concentrated under reduced pressure. The solution was quenched by pouring it into a mixture of ice water (100 mL), and then extracting with EtOAc (3×100 mL). The organic layers were combined, dried over sodium sulfate, and filtered. The solution was evaporated to dryness, and adsorbed onto silica gel. The crude product was purified using column chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexanes, to provide 6-bromo-1H-indazole (4.6 g, 18 mmol, 76% yield). LCMS (M+H) 197.9 calc. for C7H5BrN2 197.0, 1H NMR (400 MHz, CD3OD): δ ppm 8.03 (s, 1H), 7.67-7.72 (2H, m), 7.24-7.26 (m, 1H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1>>[CH3:27][C:28]1[C:32]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. White solid. MS (ESI): 474.2 (MH+)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:24]([CH3:25])=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:26])[CH2:11][N:10]=3)=[C:19](I)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:27][C:28]1[CH:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[O:30][N:29]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:24]([CH3:25])=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:26])[CH2:11][N:10]=3)=[C:19]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[CH:32]=3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC1=C2c3cccc(I)c3CCN2C(=O)CN=C1n1cnc(C2CC2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1=C2c3cccc(-c4cc(C)no4)c3CCN2C(=O)CN=C1n1cnc(C2CC2)c1
Temperature: 140 °C
Reaction time: 0.02 h
Yield: 56.9 %

Procedure:
Example 107. A mixture of 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (8 mg, 17 μmol), 3-methyl-5-(tributylstannyl)isoxazole (10 mg, 26 μmol) and Pd(PPh3)4 (1.0 mg, 0.9 μmol) in dioxane (0.2 mL) is heated to 140° C. for 1.5 h under N2 in a microwave reactor. The mixture was then concentrated in vacuo the residue obtained was purified by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 8% MeOH/CO2 for 1 min, then from 8% MeOH/CO2 to 13% MeOH/CO2 in 6 min; then from 13% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (4 mg) as a beige solid. UPLC-MS: MS 414.2 (M+H+); UPLC rt 0.88 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.74-0.88 (m, 4 H); 1.74-1.91 (m, 1 H); 2.18 (s, 3 H); 2.42 (s, 3 H); 2.81 (td, J=14.68, 5.27 Hz, 1 H); 3.17 (td, J=13.49, 3.64 Hz, 1 H); 3.45 (m., 1 H); 3.91-4.02 (m, 2 H); 4.70 (d, J=10.79 Hz, 1 H); 6.32 (s, 1 H); 6.95 (s, 1 H); 7.45 (t, J=7.65 Hz, 1 H); 7.56 (d, J=7.78 Hz, 1 H); 7.66-7.76 (m, 2 H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:4][CH:3]([CH2:2][CH3:6])[CH2:5][O:7][C:6](=[O:8])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:18](=[O:19])[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)COC(=O)[C@@H](NC(=O)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 136.4 %

Procedure:
To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.