Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]([C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])[CH:24]=3)=[CH:19][CH:18]=2)=[N:14][N:13]=1.C(N(CC)CC)C>C1COCC1>[C:1]([NH:10][CH2:11][C:12]1[O:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]([C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])[CH:24]=3)=[CH:21][CH:22]=2)=[N:14][N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of benzoyl chloride (6.3 μl) in THF (1 ml) was added dropwise to 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (18.8 mg) and triethylamine (7.5 μl) in THF (4 ml). The reaction was stirred at room temperature for 16 hours, the solvent evaporated, the residue dissolved in water (10 ml) and extracted with DCM (2×10 ml). The combined organics were reduced to dryness under vacuum, the residue dissolved in methanol and the solution applied to a bond-elut (aminopropyl, 1 g), eluting with further methanol. The eluent was reduced to ca 10 ml in vacuo and passed through a bond-elut (SCX, 2 g), eluting with methanol. The solvent was evaporated from the eluent under vacuum. The residue was applied to a bond-elut (silica, 2 g) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent 4′-{5-[(benzoylamino)methyl]-1,3,4-oxadiazol-2-yl}-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]S(C)(=O)=O)=[CH:22][CH:21]=2)=[C:13]([CH3:31])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+].O>C1COCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:13]([CH3:31])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C)c1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(O)cc2)c(C)c1)C(=O)O
Yield: 10.6 %

Procedure:
Ethyl 2-ethoxy-3-[3-methyl-4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]propanoate (0.150 g; 0.330 mmole) was dissolved in THF. 5M sodium hydroxide (10 eqv) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (20-100%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.012 g (8% yield) of the desired product.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[C:5]([N+:11]([O-])=O)[C:3]=1[NH2:4]>[Pd].C(O)C>[NH2:11][C:5]1[C:6]([F:10])=[CH:7][C:8]([F:9])=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: Nc1c(F)c(F)cc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1c(F)cc(F)c(F)c1N
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol was hydrogenated overnight at atmospheric pressure, filtered under nitrogen and concentrated to provide 1,2-diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a purple crystalline solid; MS M+ 162.7, +41. +82 (+ACN, +2ACN). (calcd for C6H5F3N2: 162.11).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:20])=[CH:16][C:15]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:29]([C:15]1[CH:16]=[C:17]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[O:20])[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH:5]([CH3:33])[C:4]([OH:34])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(C)Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1)C(=O)O

Procedure:
A solution of Example 202 (15 mg, mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was adjusted to pH=4, extracted with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After the filtrate was concentrated, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-2-methyl-propionic acid as a racemate (13 mg, 90%). 1H NMR (DMSO): 12.48 (br s, 1H), 9.35 (br s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.34-7.32 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.10 (d, J=7.6 Hz, 1H), 6.45 (s, 1H), 2.74 (m, 1H), 2.65 (m, 1H), 2.31 (m, 2H), 1.26 (s, 9H), 0.99 (d, J=6.8 Hz, 3H); MS (ESI) m/z: 455 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11]([O-])(O)=O.[Na+]>CO.ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH3:11][O:8][C:6]1[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C([O-])O
Agent: [Ti+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 5,5-dimethyl-cyclohexane-1,3-dione (80.0 g, 0.57 mol) in anhydrous methanol (600 mL) was treated with a 1M solution of titanium chloride (TiCl4) in dichloromethane (17.2 mL). After stirring 1 hour at room temperature, the mixture was slowly poured into cold 5% NaHCO3 solution and extracted with diethyl ether (450 mL×6). The organic layers were collected, washed with brine, dried on Na2SO4 and evaporated to dryness affording the title compound (81.5 g, 92% yield) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([O:21]CC)=[O:20])=[C:11]2[CH3:24])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=[O:20])=[C:11]2[CH3:24])[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccc(Cl)cc1
Yield: 105 %

Procedure:
To a mixture of ethyl 1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-indole-3-carboxylate (210 mg, 0.61 mmol) in MeOH/H2O (6 mL/2 mL) was added KOH (340 mg, 6.1 mmol) at room temperature. The reaction was refluxed overnight. Then the mixture was adjusted to Ph=4 with 1 N HCl and extracted with EtOAc (3×). The combined organic extract were combined and concentrated in vacuo to afford the title compound as a yellow solid (200 ing, yield 105%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[NH:1][C:24](=[O:25])[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(F)cc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Cl)cc32)CC1
Temperature: 50 °C

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-fluorophenyl)amino]-1-piperidinecarboxylate (D3) (0.87 mmol, 300 mg) was dissolved in 5 ml of tetrahydrofuran and carbonyldiimidazole (1,1′-(oxomethanediyl)bis-1H-imidazole) (3 eq., 2.6 mmol, 440 mg) was added at room temperature; the mixture was refluxed at 50° C. overnight. The mixture was cooled to room temperature, THF evaporated and it was diluted in ethyl acetate/H2O/NaHCO3 (saturated solution); the two layers were separated and the aqueous phase was extracted with ethyl acetate (2×); the organic phases were combined and washed with water and NaHCO3 (saturated solution), they were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (methanol-NH3-dichloromethane) to yield the title compound, 170 mg 53%, M+−H=368.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:26]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][C:21]([O:23]CC)=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[C:3]([NH:18][CH:19]([C:26]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(CC(=O)O)Nc2nc(-c3n[nH]c4ncc(F)cc34)ncc2F)CCCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of racemic ethyl 3-[[5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate, 149a, (0.110 g, 0.256 mmol) in THF (30 mL) was added a solution of lithium hydroxide hydrate (0.043 g, 1.022 mmol) in H2O (20 mL). The reaction mixture was stirred at 70° C. overnight. The organic solvent was removed under reduced pressure and the remaining aqueous phase was used directly in the purification via preparatory HPLC. The resulting HPLC fractions were extracted with EtOAc. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the desired product: 1H NMR (400 MHz, MeOD) δ 8.64 (dd, J=8.4, 2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 5.19 (d, J=8.7 Hz, 1H), 2.78 (qd, J=15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H), 1.48 (dd, J=11.8, 6.0 Hz, 1H), 1.36 (dt, J=12.0, 6.0 Hz, 1H), 1.11 (s, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.37 min, (M+H) 403.22.
Reaction SMILES: Cl.[C:2]([C:12]1[CH:29]=[CH:28][C:15]([CH2:16][NH:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1)#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[C:2]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]([C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:29]=1)#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCCCCCC#Cc1ccc(CNc2cccc(C(=O)OC)c2)cc1
Agent: Cl
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCCCC)c2cccc(C(=O)OC)c2)cc1

Procedure:
The titled compound was prepared following the procedure G using methyl 3-[(4-dec-1-yn-1-ylbenzyl)amino]benzoate hydrochloride and hexanoyl chloride as a pale yellow oil (74%). 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.38 (m, 1H), 7.30 (d, J=7.9 Hz, 2H), 7.08 (m, 3H), 4.88 (s, 2H), 3.93 (s, 3H), 2.39 (t, J=7.0 Hz, 2H), 2.04 (t, J=7.2 Hz, 2H), 1.60 (m, 4H); 1.44 (m, 2H), 1.35-1.15 (m, 12H), 0.89 (t, J=6.8 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H), M1(ESI): 476.5. HPLC, Rt: 6.17 min (Purity: 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5](/[CH:11]=[CH:12]/[CH:13]=O)=[C:4]([F:15])[CH:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:11]=[CH:12][CH:13]=[N:8]2)=[C:4]([F:15])[CH:3]=1
Reactant: O=C/C=C/c1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1cc(Br)cc2ncccc12
Temperature: 120 °C
Yield: 55.5 %

Procedure:
A glass microwave reaction vessel was charged with (E)-3-(4-bromo-2-fluoro-6-nitrophenyl)acrylaldehyde (35 mg, 0.128 mmol), iron powder (0.018 mL, 2.55 mmol, Aldrich) and ammonium chloride (6.83 mg, 0.128 mmol, Aldrich) in ethanol (1 mL). The reaction mixture was stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 5 min. The mixture was filtered through a pad of Celite® (diatomaceous earth), washed with EtOAc. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to give 7-bromo-5-fluoroquinoline (16 mg, 0.071 mmol, 55.4% yield). 1H NMR (300 MHz, CDCl3) δ 7.20-7.34 (m, 1H) 7.59-7.74 (m, 1H) 7.90 (d, J=8.48 Hz, 1H) 8.58 (d, J=1.61 Hz, 1H) 8.95 (d, J=2.34 Hz, 1H). m/z (ESI, +ve ion) 227.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH3:9][NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12]>>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:11]([NH:10][CH3:9])=[O:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(Br)cn1
Product: CNC(=O)c1ccc(-c2ccc(F)nc2)cc1

Procedure:
This compound was prepared from 5-bromo-2-fluoropyridine and {4-[(methylamino)carbonyl]phenyl}boronic acid using procedures analogous to those for Example 18, step 1. Analytic LCMS (M+H)+: m/z=231.1.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)#[N:6].O>ClCCl>[C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)#[N:6]
Reactant: COc1ccc(-c2ccc(C#N)s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(-c2ccc(O)cc2)s1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A 1M solution of boron tribromide in dichloromethane (55 cm3) was added dropwise to a solution of 2-cyano-5-(4-methoxyphenyl)thiophene (2.3 g) and dichloromethane (80 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution was stirred overnight and water (100 cm3) added. The organic layer was separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers were washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue was purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 1.4 g of g 2-cyano-5-(4-hydroxyphenyl)thiophene.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:13])[CH2:6][C:7]1[N:11]=[C:10]([NH2:12])[S:9][N:8]=1)[CH:2]=[CH2:3].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[CH2:1]([O:4][C:5](=[O:13])[CH2:6][C:7]1[N:11]=[C:10]([NH:12][C:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH2:29][CH2:28][CH2:27][N:26]3[S:23]([C:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=3[O:15][CH3:14])(=[O:25])=[O:24])=[CH:31][CH:32]=2)=[O:37])[S:9][N:8]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Reactant: C=CCOC(=O)Cc1nsc(N)n1
Product: C=CCOC(=O)Cc1nsc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)n1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (5-amino-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded (5-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester, which was hydrolyzed to (5-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-[1,2,4]thiadiazol-3-yl)-acetic acid in step 4, MS (ISP): m/e=501.1 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[NH2:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=[C:7]2[NH2:13]
Reactant: CC(C)(C)N
Reactant: Nc1nc(Cl)nc2c(Br)cccc12
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(N)c2cccc(Br)c2n1
Temperature: 120 °C
Yield: 106.9 %

Procedure:
A microwave vial was charged with 8-bromo-2-chloroquinazolin-4-amine (484a; 0.109 g, 0.422 mmol) and tert-butylamine (Aldrich; 1.33 mL, 12.65 mmol). The slurry was heated to 120° C. in a biotage initiator microwave for 30 min. 0.5 mL NMP was added to give a solution and the reaction was heated to 120° C. in a biotage initiator microwave for 30 min. The reaction was heated to 150° C. in a biotage initiator microwave for 30 min. The reaction was heated to 160° C. in a biotage initiator microwave for 30 min and then was heated to 170° C. in a biotage initiator microwave for 30 min. The reaction was partitioned between water and EtOAc. The organic layer was washed with water 2 times, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-N2-(tert-butyl)quinazoline-2,4-diamine (0.133 g, 0.451 mmol, quant. yield) as a brown foam: 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (1H, dd, J=7.5, 1.3 Hz), 7.48 (1H, d, J=7.8 Hz), 6.92 (1H, t, J=7.8 Hz), 5.27 (2H, br. s.), 5.02 (1H, br. s.), 1.55 (9H, s). m/z (ESI, +ve ion) 295.0/297.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c(OC)c1
Yield: 59 %

Procedure:
Prepared from VII and 2,4-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 59%; orange solid; mp 255-257° C.; IR (KBr) νmax/cm−1 3401, 3081, 2948, 2837, 2233, 1600, 1565, 1540, 1525, 1505, 1443, 1417, 1329, 1278, 1231, 1203, 1159, 1132, 1088, 1030, 959, 915; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 7.98 (s, 1H), 7.83 (d, 1H, J=9.0 Hz), 6.95 (m, 1H), 6.67 (s, 1H), 6.58 (d, 1H, J=9.0 Hz), 3.78 (s, 3H), 3.73 (s, 3H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0856.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:8][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)=[CH:13][CH:12]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of p-aminophenol (0.200 g, 1.83 mmol), 4-trifluoromethylbenzyl alcohol (025 ml, 1.83 mmol) and triphenylphosphine (0.529 g, 2.02 mmol) in 5 ml anhydrous tetrahydrofuran was added diethyl azodicarboxylate (0.318 ml, 2.02 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. It was then diluted with 70 ml ethyl acetate and the resulting solution was washed sequentially with 50 ml saturated aqueous sodium bicarbonate solution, 50 ml water and 50 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 8:2 hexane/ethyl acetate to yield the title compound as an off-white solid (0.272 g, 55% yield). MS: 284.1 (M+1)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C(O)(C)C.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncccn1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccn2)CC1
Yield: 36.7 %

Procedure:
4-Amino-1-t-butoxycarbonylpiperidine from Step A, (1.9 g, 9.5 mmol), 2-chloropyrimidine (1.1 g, 9.5 mmol) and DIPEA (3.3 mL, 19 mmol) were combined in isopropanol (10 mL) and the mixture was refluxed for 24 h. The mixture was cooled, diluted with methylene chloride (100 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated. FC (60 g silica, 1/1 hexanes/ethyl acetate) afforded the title compound (0.97 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>CN(C)C1C=CN=CC=1.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:5]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccccc1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccccc1Br
Yield: 77710.2 %

Procedure:
A solution of o-bromobenzoic acid (1 g), N, N'-dicyclohexyl carbodiimide (1.129 g), t-butanol (405 mg) and 4-dimethylaminopyridine (61 mg) in dry ether (20 ml) was stirred at room temperature for 18 h. The resulting precipitate was filtered off and the filtrate evaporated to give a colourless solid which was triturated under petroleum ether (40°-600°) (20 ml) and filtered. The filtrate was evaporated to give a pale yellow oil (0,994 g). b.p. 80°-84°/0.35 mmHg.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, light yellow solid (23 mg, 26%), MS (ISP) m/z=350.5 [(M+H)+], mp 298° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 50 °C
Yield: 102.3 %

Procedure:
1-(4-Benzyloxyphenyl)-4,4-dimethyl-cyclohexanol (4.14 g, 13.3 mmol) was dissolved in ethanol (80 mL) by stirring after which concentrated hydrochloric acid (8 ml) was added. This stirred mixture was heated to 50° C. for 1.5 hours. The solvent was removed under reduced pressure. The residue was basified with ammonium hydroxide, extracted three times with EtOAc and the organic extracts combined and concentrated to afford 1-benzyloxy-4-(4,4-dimethylcyclohex-1-enyl)-benzene as a white solid (3.98 g, 99%).