Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13]([CH3:15])C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26]C=1N>C1C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[F:20])[N:13]([C:15]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=1[F:22])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: COc1ccc(N)c(F)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1Br
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(OC)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-dimethylaminoacrylate (1.09 g) and 2-fluoro-4-methoxyaniline (0.51 g) are dissolved in benzene (10 ml), and the mixture is allowed to stand at room temperature for 2 hours. The reaction mixture is washed with diluted hydrochloric acid and saturated aqueous sodium chloride, and dried over sodium sulfate. After distilling off the solvent, the residue is dissolved in anhydrous dioxane (20 ml) and thereto is added 60% sodium hydride (0.14 g). The mixture is stirred at room temperature for one hour and further refluxed for one hour. After cooling, the reaction mixture is poured into saturated aqueous ammonium chloride under ice-cooling. The precipitated crystals are separated by filtration, washed with water, purified by silica gel column chromatography (solvent, dichloromethane:methanol=80:1), and then recrystallized from ethanol to give ethyl 6,7-difluoro-1-(2-fluoro-4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.59 g) as pale yellow needles, m.p. 170°-171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13]>C(OCC)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][NH:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: N#Cc1cccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from 3-amino-benzonitrile (Fluka) and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 138-142° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].C(N(C(C)C)C(C)C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH:12][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: NNc1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NNc1ccc([N+](=O)[O-])cc1Br
Yield: 60.7 %

Procedure:
To a stirred and chilled (0°) solution containing 200 g (0.86 mol) of 2-bromo-4-nitrophenylhydrazine (m.p. 143°-145°) and 116.8 g (0.9 mol) of ethyldiisopropylamine in 1000 ml of tetrahydrofuran was added dropwise 108.5 g (0.9 mol) of pivaloyl chloride. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated to dryness under reduced pressure. The residue was treated with water, filtered and recrystallized from ethanol to give 165 g (52%) of product as a light yellow solid; m.p. 145° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:56]([CH:58]([CH2:61][CH3:62])[CH2:59][NH2:60])[CH3:57]>CN(C=O)C>[CH2:56]([CH:58]([CH2:61][CH3:62])[CH2:59][NH:60][C:11](=[O:13])[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:14])[CH3:57]
Reactant: CCC(CC)CN
Reactant: O=C(O)Cn1cccc([N+](=O)[O-])c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)CNC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product 2-(3-nitro-2-oxopyridin-1(2H)-yl)acetic acid (˜14.7 mmol), 4.71 g (14.7 mmol) of TBTU, 1.98 g (14.7 mmol) of HOBT and 4.99 mL (29.3 mmol, 2 eq) of DIPEA are dissolved in 60 mL of DMF (argon atmosphere). 1.97 mL (14.7 mmol) of 2-ethyl-butylamine ((→pH=6) and another eq DIPEA (→pH=8) are added. After 1 h a half eq DIPEA is further titrated and stirred overnight at RT. If the TLC control shows incomplete conversion, it is stirred for further 3 h at 45° C. The solvent is removed in vacuo and the residue is taken up in 500 mL of DCM/MeOH (8/2). It is subsequently washed with 10% citric acid (3×100 mL), saturated NaHCO3 solution (3×100 mL) and brine (75 mL). The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The crude product (3.5 g) is treated with 10 mL of ethyl acetate, 30 mL of PE (40-60) is added and stirred for 15 min at RT. The solid is filtered off, washed with some amount of PE and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(CCc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1CCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 84.9 %

Procedure:
In 300 ml of methanol, 13 g of 4-(2-nitrophenyl)-2-phthalimidobutyric acid is catalytically reduced at ambient temperature and under atmospheric pressure with use of 3 g of 5% palladium-carbon as a catalyst. After the calculated amount of hydrogen is absorbed, the insoluble material is separated by filtration, and washed four times with 300 ml of acetone. The acetone washings and the methanol portion are combined and concentrated under reduced pressure. The residue is admixed with 50 ml of ethanol, and the crystals which separate out are collected by filtration to give 10.1 g of 4-(2-aminophenyl)-2-phthalimidobutyric acid as yellow prisms. m.p. 198°-203° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[N:9][NH:8][C:7](=[O:11])[CH:6]=1.C[O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:21][CH:20]([N:8]2[C:7](=[O:11])[CH:6]=[C:5]([O:4][C:3]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:2]=3[Cl:1])[CH:10]=[N:9]2)[C:19]([OH:28])=[O:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=c1cc(Oc2cccc(Cl)c2Cl)cn[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2Cl)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 19 steps 4-5, starting from 5-(2,3-dichloro-phenoxy)-2H-pyridazin-3-one alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (12 g, 78% for the final step); LC-MS: 307 [M+1]+, tR=2.50 min. HPLC: 30.31% at 214 nm, 90.71% at 254 nm, tR=3.81 min. 1H NMR (300 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.63 (d, 1H, J=2.1 Hz), 5.79 (d, 1H, J=10.2 Hz), 3.95 (d, 1H, J=12.3 Hz), 3.58 (d, 1H, J=3.3 Hz), 2.04˜1.91 (m, 2H), 1.64˜1.49 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH2:21][OH:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)#[N:2].[CH3:28][Sn:29]([N:32]=[N+:33]=[N-:34])([CH3:31])[CH3:30]>>[CH3:28][Sn:29]([N:32]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:20]([CH2:21][OH:22])=[C:19]([Cl:23])[N:18]=[C:17]3[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[N:2][N:34]=[N:33]1)([CH3:31])[CH3:30]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Temperature: 115 °C
Reaction time: 41 h

Procedure:
1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (766 g), trimethyl tin azide (766 g) and xylenes (7.90 L) were charged to a 12 liter round-bottomed flask equipped with mechanical stirrer, condenser with N2 inlet and thermometer contained in a heating mantle. The slurry was heated to 115° C., giving a clear solution, and held for 41 hours. The resulting slurry was cooled to room temperature and the crude product isolated by vacuum filtration, washed with toluene (800 ml) and dried in vacuo at ~50° C. overnight. The crude product (1202 g) was charged to a 12 liter round-bottomed flask and slurried at 105° C. with toluene (70 L). The slurry was cooled to 50° C. and the product isolated by vacuum filtration, washed with one liter of toluene and dried in vacuo at 50° C. overnight. Yield: 1071 g, 94%. M.P.: 211°-214° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][O:6][CH2:5]1.[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]1)([CH3:13])[CH3:12]>>[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C@@H:16]([NH:19][CH:9]2[CH2:8][CH2:7][O:6][CH2:5][CH:4]2[CH2:3][O:2][CH3:1])[CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: COCC1COCCC1=O
Product: COCC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1

Procedure:
The title compound was prepared by reductive amination of 3-(methoxymethyl)tetrahydro-4H-pyran-4-one with (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine using the procedure described for Example 5. MS calculated for C27H40F3N3O3: (M+H) 512; found 512.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([Cl:20])=[C:15]([O:21][CH2:22][C:23]#[N:24])[CH:14]=[CH:13]2.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]=3[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]#[N:24]
Reactant: CCCCC(=O)Cl
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4o3)ccc2c1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC#N)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 3 of Example 23, 2-{[6-(1-benzofuran-2-yl)-1-chloro-2-naphthyl]oxy}acetonitrile (6.12 g, 18.3 mmol) was acylated with valeryl chloride (2.2 mL, 19 mmol) in presence of tin (IV) chloride (2.2 mL, 19 mmol) in methylene chloride (37 mL). Purification by HPLC using 20% ethyl acetate in hexane as the mobile phase yielded 2-{[1-chloro-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile as a yellow waxy solid (2.55 g), mp 86-89° C. Mass spectrum (+ESI, [M+H]+) m/z 418. 1HNMR (500 MHz, DMSO-d6): δ8.55 (d, 1H, J=1.4 Hz), 8.3 (d, 1H, J=8.9 Hz), 8.25 (d, 1H, J=9.2 Hz), 8.0-8.05 (m, 2H), 7.75-7.8 (m, 2H), 7.4-7.5 (m, 2H), 5.5 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.75 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C12H20ClNO3: Calculated: C, 71.85; H, 4.82; N, 3.35. Found: C, 71.73; H, 4.59; N, 3.15.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:36])([F:24])[F:35])=[CH:31][N:30]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C(F)(F)F)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-trifluoromethyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:10]([O:14][C:15](=[O:18])[CH2:16][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
A mixture of 4-iodobenzylamine (5.0 g, 21.5 mmol), tert-butylbromoacetate (4.19 g, 21.5 mmol), potassium carbonate (3.55 g, 21.5 mmol) in 40 mL of 1:1 toluene/water was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate (100 mL×3) and the combined organic phase was washed with brine, dried over sodium sulfate, and evaporated to give an oil. Chromatography on silica gel gave 2.3 g (31%) of N-(4-iodobenzyl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:21][C:22]4[N:27]5[C:28]([C:31]([O:33]CC)=O)=[N:29][N:30]=[C:26]5[CH2:25][O:24][C:23]=4[N:36]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:44]>[OH-].[NH4+]>[C:31]([C:28]1[N:27]2[C:22]3[CH:21]=[C:20]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:9]5([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12]5)=[CH:14][CH:15]=4)=[N:36][C:23]=3[O:24][CH2:25][C:26]2=[N:30][N:29]=1)(=[O:33])[NH2:44]
Reactant: CCOC(=O)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(N)=O)CO4)cc2)CCC1
Temperature: 100 °C
Yield: 57.4 %

Procedure:
A suspension of ethyl 7-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazine-1-carboxylate (70 mg, 0.123 mmol) and ammonium chloride (10 mg, 0.19 mmol) in ammonium hydroxide (1 ml) was heated to 100° C. for 10 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 10% ethyl acetate in cyclohexane) to give the title compound (38 mg, 13%). LCMS (Method D): RT=1.347 min, M+1=539. 1H-NMR (500 MHz, CD3OD) δ 9.10 (1H, s), 7.47-7.40 (1H, bs), 7.40-7.37 (2H, d), 7.32-7.27 (6H, m), 5.59 (2H, s), 2.59-2.39 (4H, m), 2.14-2.01 (1H, m), 1.88-1.76 (1H, m), 1.44-1.33 (9H, bs).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:7][OH:8])=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(Cc1ccc(F)cc1)c1ccncc1

Procedure:
Sodium acetate (36.1 g; 0.44 mol) and hydroxylamine hydrochloride (22.0 g; 0.32 mol) were introduced into a suspension of a2 (21.5 g; 0.1 mol) in 50% strength methanol (350 ml). The reaction mixture was stirred under reflux for 1 h. When the clear solution was cooled in an ice bath, a3 was obtained as a beige precipitate which was filtered off, washed with H2O and dried under reduced pressure over P2O5.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]=O.[OH-].[Na+]>C(O)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH3:32])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCCCc1ccc(C#Cc2ccc(CN(C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Yield: 22.3 %

Procedure:
A solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (305 mg; 0.73 mmol), formaldehyde (Aldrich, 50 μl; 1.84 mmol) and formic acid (2.5 mL) was stirred under microwaves at 100° C. for 5 min. The reaction mixture was then poured into an aqueous solution of NaOH 1M and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude (257 mg, yellow oil) by flash chromatography on silicagel afforded 70 mg of the title compound as a yellow powder. HPLC, Rt: 5.84. min (purity=100%). 1H NMR (CDCl3) δ: 7.4 (m, 4H), 7.3 (s, 1H), 7.2 (m, 4H), 6.9 (t, J=7.8 Hz, 1H), 6.75 (m, 1H), 4.4 (s, 2H), 2.92 (s, 3H), 2.5 (t, J=7.7 Hz, 2H), 1.5 (m, 2H), 1.25 (m, 2H), 0.8 (t, J=7.53 Hz, 3H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:20][CH3:21])=[N:9]1)C1C=CC=CC=1.C(O)=O>[C].[Pd].C(O)C>[CH2:20]([O:19][C:10]1[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:8][N:9]=1)[CH3:21]
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCC
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)Cc1c[nH]nc1OCC
Yield: 54.1 %

Procedure:
A mixture of ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-ylacetate (7.50 g), 5% palladium-carbon (15.0 g), formic acid (50 ml) and ethanol (100 ml) was refluxed for 1 hour. After cooling, the palladium-carbon was removed by filtration, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate solution, and with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (2.79 g, yield 54%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:29][B:28](B2OC(C)(C)C(C)(C)O2)[O:27]1.C(N(CC)CC)C.C([O-])(=O)C.[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:5]1[N:6]=[CH:7][C:2]([B:28]([OH:29])[OH:27])=[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:18]=2)[CH:4]=1)[CH3:13]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(Br)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(B(O)O)cn1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
In a 100 mL flask 1-(5-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-yl)-3-ethylurea (Intermediate 97, 1.28 g, 3.14 mmol) was dissolved in 1,4-dioxane (15 mL) at 40° C. and degassed with argon. Bis(triphenylphosphine)palladium chloride (0.221 g, 0.31 mmol) was added and allow it to react for 10 minutes while heating at 40° C. 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.394 g, 9.43 mmol) was added and stirred for 10 minutes while heating at 100° C. Triethylamine (1.314 mL, 9.43 mmol) and potassium acetate (0.925 g, 9.43 mmol) were added and the solution was heated at 100° C. for 15 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was back extracted three times with ethyl acetate. The organic layers were combined and washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure, and purified by column chromatography (Silica gel, 0-10% MeOH in CH2Cl2). Isolation gave 400 mg of the title compound as an off-white solid.
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][C:7](=[O:33])[CH2:8][NH:9][C@@H:10]([C:14]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22](=[O:31])[C:21]3[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=3)[N:15]=2)[CH:11]([CH3:13])[CH3:12])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.CCN(CC)CC.[C:47]1([CH3:56])[C:48]([C:53](Cl)=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1>C(Cl)Cl>[C:47]1([CH3:56])[C:48]([C:53]([N:9]([CH2:8][C:7](=[O:33])[CH2:6][N:5]2[C:4](=[O:34])[C:3]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]3[C:1]2=[O:39])[C@@H:10]([C:14]2[N:23]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22](=[O:31])[C:21]3[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=3)[N:15]=2)[CH:11]([CH3:13])[CH3:12])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(CC(=O)CN1C(=O)c2ccccc2C1=O)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To 2-[(R)-1-(3-phthalimido-2-oxo-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (7.22 g, 13.3 mMol) in CH2Cl2 (50 mL) was added Et3N (2.0 mL, 14.3 mMol) and toluoyl chloride (1.9 mL, 14.4 mMol). The reaction was stirred at RT for 18 h, concentrated under vacuum, taken up in EtOAc, washed with 1 N HCl, brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography on silica gel (1% MeOH/CH2Cl2) followed by trituration with (1:1) Et2O/pet. ether, filtration and drying under vacuum gave the title compound (6.41 g, 73%) as a white solid. A side fraction (1.20 g) which contained mostly product was also obtained: 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.6 Hz, 1 H), 7.69-7.78 (m, 5 H), 7.45-7.49 (m, 3 H), 7.34 (t, 2 H), 7.25-7.29 (m, 3 H), 7.15 (d, J=8.1 Hz, 2 H), 6.19 (d, J=15.9 Hz, 1H), 5.82 (d, J=10.6 Hz, 1H), 5.12 (d, J=15.9 Hz, 1H), 4.56 (d, J=18.8 Hz, 1 H), 4.26 (d, J=18.8 Hz, 1 H), 4.09 (d, J=17.6 Hz, 1 H), 3.90 (d, J=17.6 Hz, 1H), 2.62 (n, 1 H), 2.42 (s, 3 H), 0.93 (d, J=6.8 Hz, 3 H), 0.32 (d, J=6.4 Hz, 3 H); MS (ES) m/e 661.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].[CH2:18]([NH:20][CH2:21][CH2:22][OH:23])[CH3:19]>C(Cl)Cl>[Si:14]([O:23][CH2:22][CH2:21][NH:20][CH2:18][CH3:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
DIPEA (5.48 ml, 31.38 mmol) and tert-butylchlorodimethylsilane (6.76 g, 22.42 mmol) were added to a solution of 2-(ethylamino)ethanol (1.998 g, 22.42 mmol) in DCM (39.3 ml) at room temperature. The mixture was stirred at room temperature for 20 hours, partitioned between H2O/Et2O (50 ml/50 ml). The aqeuous phase was extracted with ether (3×30 ml). The combined organic layers were concentrated under reduced pressure to give a residue which was re-dissolved in DCM (50 ml), dried (Na2SO4), filtered and concentrated under vacuum to give the title compound (3.9 g, yield: 85%).