Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][CH3:13])[CH3:11])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([N:12]([CH3:13])[C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CN[C@@H](C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@@H](c1nc2ccc(F)cc2n1-c1ccccc1)N(C)c1ncnc2[nH]cnc12
Temperature: 90 °C
Yield: 83.6 %

Procedure:
A mixture of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]methylamine (102 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (91 mg, 0.38 mmol) and DIPEA (0.33 mL, 1.9 mmol) in n-butanol (2 mL) was heated at 90° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 181 (123 mg, 84%). LCMS (Method K): RT 3.39 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.99 (1H, s), 7.90 (1H, s), 7.75 (1H, dd, J=8.81, 4.87 Hz), 7.30-7.22 (2H, m), 7.17-6.95 (5H, m), 6.73 (1H, dd, J=8.93, 2.53 Hz), 3.12 (3H, br s), 1.71 (3H, d, J=6.76 Hz)
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][C@@H:26]2[O:29]C=O)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([O:32]C=O)[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9].CO.[OH-].[Na+]>O>[OH:32][C@@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][C@H:26]([OH:29])[C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH3:9])[CH2:18]1
Reactant: COC(=O)CCCCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CCCCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 64.8 %

Procedure:
A solution of 7.2 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)pentanoic acid methyl ester, 50 ml of methanol, 50 ml of 2N methanolic sodium hydroxide solution and 10 ml of water was refluxed for 2 hr. At the end of this time, the methanol was removed under reduced pressure and 300 ml of water was added to the residue. The solution was treated with charcoal and filtered through a bed of diatomaceous earth. The solution was then cooled to 0° and with stirring acidified (pH3) by the dropwise addition of concentrated aqueous hydrochloric acid. The precipitate was filtered and dried overnight under house vacuum. Crystallization from methyl ethyl ketone gave 4 g of 5-(3α,12α-dihydroxy-5β-pregnane-20-yl)pentanoic acid, mp 191°-193°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0.0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (ethanol free) at 01 C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was dissolved in CHCl3 (30 ml) and a solution of 3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added to this at 01 C. The mixture was stirred and allowed to warm at room temperature. After 1.5 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 3.14 g (92.6%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m, 1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m, 1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21]([CH2:25][OH:26])([CH3:24])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[O:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][C:21]([CH3:24])([CH:25]=[O:26])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCC(C)(CO)CC2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCC(C)(C=O)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
A solution of oxalyl chloride (0.176 mL, 2.015 mmol) in DCM (8 mL) was cooled to −70° C. and treated with anhydrous DMSO (0.238 mL, 3.36 mmol). The resultant solution was stirred at −70° C. for 20 min and then treated with (1-(4-chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)methanol in DCM (3 mL) and stirred for 40 min. Triethylamine (0.702 mL, 5.04 mmol) was added to the reaction. Upon completion of addition, the mixture was stirred at −70° C. for 30 min and then warmed to RT. The mixture was diluted with DCM, washed with sat NaHCO3, brine, dried (Na2SO4) and concentrated to yield a residue. The residue was purified by flash chromatography on 12 g cartridge to give 1-(4-chloro-3-methoxyphenyl)-4-methylpiperidine-4-carbaldehyde (180 mg, 0.672 mmol, 40% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 9.50 (1 H, s), 7.18 (1 H, d, J=8.57 Hz), 6.47 (1 H, s), 6.43 (1 H, dd, J=8.57, 1.98 Hz), 3.82-3.89 (3 H, m), 3.27-3.36 (2 H, m), 2.93-3.03 (2 H, m), 2.03-2.12 (2 H, m), 1.57-1.67 (2 H, m), 1.11 (3 H, s).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(=O)(OC)OC.Cl.Cl[S:17]([OH:20])(=[O:19])=[O:18]>C1CCCCC1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: C1CCCCC1
Solvent: COC(=O)OC
Product: O=S(=O)(O)c1ccc(O)cc1O
Temperature: 60 °C

Procedure:
15.0 g (0.136 moles) of resorcinol, 102 g dimethyl carbonate and 68 g cyclohexane were charged under nitrogen to a 4-necked one litre reactor fitted with stirrer, thermometer and condenser attached to an HCl scrubber system. The reaction mixture was heated to 60° C. and 15.1 g (0.13 moles) of chlorosulphonic acid added over a period of 4 h with removal of hydrogen chloride gas. On completion of the addition, the reaction mixture is heated to 70-72° C. for 1 h, and then cooled to 20° C. The reaction mixture separated into two layers with the lower layer containing 2,4-dihydroxybenzene sulphonic Acid (63.2% by hplc) and resorcinol (31.5% by hplc).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:10]=[C:9](Br)[CH:8]=1.B(OC)(OC)[O:20]C>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([OH:20])[CH:10]=[C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:12]=1
Reactant: COB(OC)OC
Reactant: COC(OC)c1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1cc(O)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 45.4 %

Procedure:
To a stirring solution of 23 mL of n-BuLi (1.6 M in hexanes) in 20 mL of THF at −78° C. was added 5.31 g of 1,3-dibromo-5-(dimethoxymethyl)benzene in 80 mL of THF dropwise over a period of about 55 min. After 50 min., 3.2 mL (28.7 mmol) of B(OMe)3 was added, and the solution was stirred at −78° C. for 20 min. The cold bath was removed and stirring continued with gradual warming to r.t. After 1 h, 1 N HCl (45 mL) was added, and the aqueous layer was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated. To a stirring mixture of crude product in 70 mL of 1N NaOH at 0° C. was added 14.5 mL of H2O2 (30 wt % in H2O) dropwise. After 25 min., 5 N HCl was added to a pH=1, and EtOAc and H2O were added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided 1.92 g of 3-bromo-5-(dimethoxymethyl)phenol as a pale yellow solid with some impurity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH3:27])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: CCCO
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: CCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 75 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-propanol (6.0 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 75% yield (17.6 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (t, J=7.45 Hz, 3 H) 1.68-1.77 (m, 2 H) 2.44 (s, 3 H) 4.23 (t, J=6.65 Hz, 2 H) 6.90 (s, 1 H) 7.36 (dd, J=8.05, 7.70 Hz, 1 H) 7.42 (ddd, J=8.05, 2.34, 1.22 Hz, 1 H) 7.44 (dd, J=8.73, 1.95 Hz, 1H) 7.71 (dd, J=8.73, 0.60 Hz, 1 H) 7.71 (dd, J=1.95, 0.60 Hz, 1 H) 7.71 (dd, J=2.34, 1.53 Hz, 1 H) 7.84 (ddd, J=7.70, 1.53, 1.22 Hz, 1 H). MS (ESI+) m/z 424 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:17].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:17])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 191.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (18) (6.5 g, 19.7 mmol) in THF (30 mL) was added NaOH (1.7 g, 43.8 mmol) in H2O (60 mL) and the reaction mixture stirred at ambient temperature for 16 h. THF was subsequently removed in vacuo and the aqueous phase washed with EtOAc (50 mL). The aqueous phase was then adjusted to pH ˜2 by addition of 1M HCl and extracted with EtOAc (3×50 mL). The organics were combined dried over MgSO4 and evaporated to give the desired compound (20) as a white solid (5.7 g, 95%); AnalpH2_MeOH; Rt 2.61 min; m/z 303 (MH+); white solid
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:17][N:16]=[C:15]2[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:14]=12.[Cl-].[NH4+]>C1COCC1.CCOCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([C:18]2[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:14]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:15]3=[N:16][CH:17]=2)=[O:27])=[CH:21][CH:22]=1
Reactant: CC(C)=NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(Cl)cc3)cnc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccc(Cl)cc3)cnc21
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Acetone oxime (1.6 g) was dissolved in 50 ml of THF and potassium t-butoxide (2.46 g) was added. After stirring 30 minutes 6.2 g of 4-chloro-5-(4-chlorobenzoyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine in 50 ml of THF was added to the solution. After 30 minutes of further stirring, the reaction mixture was distributed between ether and ammonium chloride solution. Drying and evaporation of the organic phase gave a solid which was recrystallized from ethanol to give 4.91 g of product, mp 112°-113° C.
Reaction SMILES: C([N:8]1[C@H:13]([CH2:14][CH2:15][OH:16])[CH2:12][CH2:11][C@H:10]([NH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH:29]([CH3:31])[CH3:30])[N:21]=2)=[O:19])[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[OH:16][CH2:15][CH2:14][C@H:13]1[NH:8][CH2:9][C@@H:10]([NH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH:29]([CH3:31])[CH3:30])[N:21]=2)=[O:19])[CH2:11][CH2:12]1
Reactant: CC(C)n1nc(C(=O)N[C@H]2CC[C@@H](CCO)N(Cc3ccccc3)C2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)n1nc(C(=O)N[C@H]2CC[C@@H](CCO)NC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
The mixture of N-[cis-1-benzyl-6-(2-hydroxyethyl)piperidin-3-yl]-1-isopropyl-1H-indazole-3-carboxamide (276 mg, 0.66 mmol, step 9 of Example 1) and 10 wt. % palladium on carbon (30 mg) in methanol (5 mL) was stirred under hydrogen (1 atom) at room temperature for 4 h. The mixture was filtered through a pad of Celite washing with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (10:1:0.2) to give 146 mg (67%) of the title compound as a white crystal.
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>CN(C1C=CN=CC=1)C>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Product: C[C@@H](c1ccc(C#CC(C)(C)NC(=O)N(C)C)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and dimethylcarbamyl chloride with the addition of DMAP. LC-MS Method 1 tR=1.53 min, m/z=506, 448; 1H NMR (CDCl3) 1.12 (s, 3H), 1.19 (s, 3H), 1.48 (d, 3H), 1.71 (s, 6H), 2.10-2.40 (5H), 2.78 (m, 1H), 2.91 (s, 6H), 5.63 (q, 1H), 6.86 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]1([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][C:33]=2[C@H:43]2[C@H:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:45][NH:44]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([N:44]2[CH2:45][CH2:46][C@@H:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[C@@H:43]2[C:33]2[CH:34]=[C:35]([NH:38][C:39]([O:41][CH3:42])=[O:40])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[O:14])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Reactant: CCOC(=O)[C@@H]1CCN[C@H]1c1cc(NC(=O)OC)ccc1S(=O)(=O)C1CC1
Agent: Cl
Product: CCOC(=O)[C@@H]1CCN(C(=O)[C@H](Nc2cc(C(N)=O)ccc2F)c2ccc(F)c(OC)c2)[C@H]1c1cc(NC(=O)OC)ccc1S(=O)(=O)C1CC1

Procedure:
Example 81 was prepared according to the general coupling condition using 27A and 76P. 1H NMR (400 MHz, Methanol-d4) δ ppm 0.92-1.09 (m, 2H) 1.08-1.19 (m, 1H) 1.19-1.28 (m, 3H) 1.33-1.48 (m, 1H) 2.18-2.51 (m, 2H) 2.89 (dd, J=5.31, 2.27 Hz, 1H) 3.03-3.19 (m, 1H) 3.64-3.76 (m, 6H) 3.79-3.96 (m, 1H) 4.00-4.27 (m, 3H) 5.44 (s, 1H) 6.18 (d, J=2.02 Hz, 1H) 6.93-7.22 (m, 7 H) 7.27 (dd, J=8.21, 2.15 Hz, 1H) 7.66-7.75 (m, 1H) 9.48 (s, 1H), LC-MS 715 (M+H).
Reaction SMILES: [CH3:1][Mg]I.[C:4]([C:7]1[N:8]=[C:9]([CH2:33][CH2:34][CH2:35][CH3:36])[N:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])(=[O:6])[CH3:5].[Cl-].[NH4+]>O1CCCC1>[CH2:33]([C:9]1[N:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]([C:12]#[N:13])=[C:7]([C:4]([OH:6])([CH3:1])[CH3:5])[N:8]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(C(C)(C)O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1 ml of a 2M solution of methylmagnesium iodide in tetrahydrofuran was added dropwise at room temperature, whilst stirring, to a solution of 840 mg of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole [prepared as described in Preparation 5(ii)] in 15 ml of tetrahydrofuran, and the resulting mixture was stirred at 40° C. for 1 hour. The mixture was cooled, and then a saturated aqueous solution of ammonium chloride was added to it dropwise. The tetrahydrofuran layer was separated and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 539 mg of the title compound as a colorless solid, melting at 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]#[N:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C[Mg+].[Br-].[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:16])[C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[C:12]([C:17]#[N:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: CCCC(=O)Cl
Reactant: CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Mg+]
Agent: [Br-]
Product: CCCC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
The product of Step D Example 1 was reacted with MeMgBr followed by butyryl chloride using the procedure of EXAMPLE 42 Step A to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:8](O)=[O:9])=O.[CH2:16]([O:18][C:19](=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22])[CH3:17]>>[Cl:1][CH2:2][C:3]1[N:22]([C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]([O:18][CH2:16][CH3:17])=[O:27])[C:8](=[O:9])[C:7]2[C:6](=[CH:14][CH:13]=[C:12]([Cl:15])[CH:11]=2)[N:5]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Product: CCOC(=O)c1ccccc1-n1c(CCl)nc2ccc(Cl)cc2c1=O

Procedure:
2-Chloromethyl-3-(2-ethoxycarbonyl-phenyl)-6-chloro-4H-quinazolin-4-one (melting point: 195°-197° C., recrystallised from toluene) was prepared from N-chloroacetyl-5-chloroanthranilic acid and anthranilic acid ethyl ester analogously to the method in J. Amer. Chem. Soc. 68 (1946), 542.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](C)=[CH:12][CH:13]=2)[C:8]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:7]1[CH3:26])C.[Cl:28]C1C=CC=C2C=1N(CC(OC)=O)C(C)=C2SC1C=CC(Cl)=CC=1>>[Cl:28][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:6]([CH2:5][C:4]([O:3][CH3:1])=[O:27])[C:7]([CH3:26])=[C:8]2[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Reactant: COC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2cccc(Cl)c21
Product: COC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cccc(Cl)c21

Procedure:
The sub-title compound was prepared by the method of example 2 part (c) using the product from step (b). Used in step (d) without further purification or characterisation.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][CH:14]=1.O>C1COCC1.CN(C=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CCOC(C)=O>[CH3:20][O:19][C:17]1[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][CH:14]=[C:13]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[N:18]=1
Reactant: Cn1ccnn1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(-c2cnnn2C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
1-Methyl-1H-1,2,3-triazole (0.044 g, 0.530 mmol) was dissolved in THF (5.3 mL) and cooled to −78° C. n-Butyllithium solution in hexanes (0.25 mL, 0.636 mmol) was added dropwise and the solution was stirred for further 5 minutes before zinc chloride (3.18 mL, 1.591 mmol) was added. After 30 minutes at −78° C., the reaction mixture was diluted with DMF (2.1 mL), tetrakis(triphenylphosphine)palladium(O) (0.031 g, 0.027 mmol) and a solution of 6-chloro-2-methoxy-3-nitropyridine (0.1 g, 0.530 mmol) in DMF (0.53 mL) were added. The solution was stirred at 80° C. for 4 hours. After the mixture was cooled to room temperature, H2O and EtOAc were added and the phases were separated. The organic phase was washed with H2O, brine, dried (Na2SO4), filtered and the solvent was removed in vacuo. The residue was purified via Biotage silica gel column chromatography eluting with cyclohexane/EtOAc (99/1 to 50/50) to afford the title compound as a light yellow solid (51 mg, 41%).
Reaction SMILES: [CH3:1][CH:2]([NH:16][C:17](=[O:19])[CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl.N>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH:2]([NH:16][C:17](=[O:19])[CH3:18])[CH3:1])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOc1ccc(Br)cc1
Reactant: CC(=O)NC(C)Cc1ccc(C2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOc1ccc(N2CCC(c3ccc(CC(C)NC(C)=O)cc3)CC2)cc1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
3.0 mL Toluene/tert-butanol (5:1) are added to a mixture of 130 mg (0.50 mmol) N-[1-methyl-2-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (VIII.1), 100 mg (0.50 mmol) 1-bromo-4-ethoxy-benzene, 80 mg (0.83 mmol) sodium tert-butyrat, 20 mg (0.040 mmol) X-Phos and 10 mg (0.040 mmol) palladium(II) acetate. The mixture is stirred for 10 min at 150° C. under microwave irradiation in a sealed tube. After that time, the mixture is poured into 1 mL 0.1 N HCl. 1 mL conc. ammonia is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulphate and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; DCM/MeOH 19:1) to yield the desired product.