Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:33])[F:34])[O:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:27][CH2:28]1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1Cl
Product: O=C(CN1CCC(Oc2ccc(C(F)(F)F)c(Cl)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 64.3 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3-chloro-4-(trifluoromethyl)phenoxy)piperidine (279 mg, 1.0 mmol) as crude materials, 162 mg title compound was generated and yield was 65%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:11]1([O:17][C:19]2[N:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3.9 mL, 7.93 mmol, 2M solution in THF) to a solution of cyclohexanol (824 μL, 7.93 mmol) in THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction by addition of saturated aqueous NaHCO3 (100 mL) and extract the aqueous phase with DCM (3×100 mL). Wash the combined organic extracts with brine (100 mL), dry over MgSO4 and concentrate in vacuo to obtain the desired intermediate as a yellow solid (1.04 g, 71%).
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:24])[N:15]([C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:25]>CO>[C:18]1([C@@H:16]([N:15]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]([NH2:25])[C:12]=3[N:13]=[C:14]2[NH2:24])[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](c1ccccc1)n1c(N)nc2c(Cl)nc3ccccc3c21
Reactant: N
Agent: Br
Solvent: CO
Product: C[C@@H](c1ccccc1)n1c(N)nc2c(N)nc3ccccc3c21

Procedure:
4-Chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide (4.0 g, 12 mmol) was treated with ammonia (65 mL of a 7 N solution in methanol) according to the method in Part D of Example 44. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:3.8:96). The chromatographed product was washed with diethyl ether several times and dried in a vacuum oven to provide 285 mg of 1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline-2,4-diamine as a brown solid, mp 135-140° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 48 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1-methylpiperazine instead of thiomorpholine to the title compound (SiO2, dichloromethane:(dichloromethane:methanol:ammonia=70:27:3)=92:2 to 80:20, 117 mg, 48%) which was obtained as an off-white solid. MS: m/e=432.4 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21](Cl)=[O:22]>ClCCl>[Br:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:22]
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CC(Br)/C=C/C(=O)Cl
Solvent: ClCCl
Product: CC(Br)/C=C/C(=O)N1CCN(c2ccnc3ccccc23)CC1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
4-piperazin-1-ylquinoline (21.3 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (0.5 ml), TEA (20.9 μl, 1.5 mmol) followed by (E)-4-bromopent-2-enoyl chloride (29.6 mg, 0.15 mmol) were added, the mixture was shaken for 10 minutes, diluted with dichloromethane, washed with 5% sodium bicarbonate solution, water and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 7 mg of a solid (0.019 mmol, 19%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[NH2:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:21])=[O:5]
Reactant: NC[C@@H]1CCCO1
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NC[C@@H]1CCCO1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available (S)-2-aminomethyltetrahydrofuran using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 1.50-1.58 (m, 2H), 1.66-0.191 (m, 3H), 3.13-3.29 (m, 2H), 3.39-3.46 (m, 1H), 3.60-3.67 (m, 1H), 3.85-3.94 (m, 1H), 7.69-7.82 (m, 3H), 8.03 (t, J=5.8 Hz, 1H), 11.42 (br s, 1H). MS (ESI+) m/z 515 (M+H)+. Anal. calcd. for C24H26F4N2O4S: C, 56.02; H, 5.09; N, 5.44. Found: C, 55.98; H, 5.05; N, 5.48.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)COC)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f51) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14]([NH:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1.[CH:26]1([C:29]2[NH:33][N:32]=[C:31]([NH2:34])[CH:30]=2)[CH2:28][CH2:27]1>C(O)CCC>[Cl:8][C:7]1[C:2]([NH:34][C:31]2[CH:30]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[NH:33][N:32]=2)=[N:3][C:4]([C:9]2[S:13][C:12]([S:14]([NH:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[N:5][CH:6]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 11.8 %

Procedure:
A mixture of tert-butyl 2-(5-(4-bromo-5-chloropyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (179 mg, 0.38 mmol, 1.0 eq) and 5-cyclopropyl-1H-pyrazol-3-amine (92 mg, 0.76 mmol, 2.0 equiv.) in n-butanol was refluxed for 2 h, The reaction was cooled down and extracted with EA and the combined layers were dried (Na2SO4), filtered and purified by silica gel chromatography (EA/PE 1:2) to afford tert-butyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (23 mg, 12%). LC-MS (m/z)=512 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2cc(F)ccc2F)c2ccccc12
Yield: 92.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.06 g of 2,5-difluorobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.46 g of 1-(2,5-difluorobenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(OC)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1
Product: COc1ccc(-c2ccc(OC)c(CN(C(=O)c3sc4ccccc4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
Biaryl amine 25 (212 mg, 0.46 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (108 mg, 0.46 mmol) using Method D to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29]>N1CCCCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][C:21]2=[O:29])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)OC)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)OC)c1C
Temperature: 10 °C
Yield: 75.1 %

Procedure:
5-Formyl-4-(2-methoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (80.2 g), 2-oxindole (37.9 g) and ethanol (300 mL) were warmed to 70° C. in a 500 mL, 3-neck round bottom flask equipped with mechanical stirring and a reflux condenser. Piperidine (1.3 g) was added and the mixture was refluxed for 4 hours. The mixture was cooled to 10° C. and the orange precipitate collected by vacuum filtration and washed with 30 mL of ethanol. The solid was slurry-washed in 150 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 81.7 g (75%) of 4-(2-Methoxycarbonylethyl)-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as an orange solid.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.C(O)=O>C1(C)C=CC=CC=1>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:8][CH2:9]2)[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=COC)CC2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1

Procedure:
In 500 ml of toluene was dissolved 50.0 g (171 ml ) of the crude 1-methoxy-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butene obtained by the procedures in the fourth step, 78.7 g (1710 mmol) of formic acid was added thereto, and then they were heated to reflux for 4 hours. The reaction mixture was washed with 300 ml of saturated aqueous sodium bicarbonate solution twice and with 500 ml of water five times, and the solvent was distilled off under a reduced pressure to obtain 45.1 g of a crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.CN1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13]([CH:10]2[CH2:12][CH2:11]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)C2CC2)cc1Br
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methylaniline (100 mg), cyclopropanecarbonyl chloride (98 mg) and N-methylmorpholine (0.12 ml) in dry dichloromethane (2 ml) was stirred at 20 C for 18 h. The mixture was then partitioned between saturated sodium bicarbonate solution and dichloromethane. The dried extracts were evaporated giving a solid which was used without purification in the next synthetic step (120 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15]OCC>>[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CCOC=C(C(=O)OC)[N+](=O)[O-]
Product: COC(=O)C(=Cc1c[nH]c2cc(C)ccc12)[N+](=O)[O-]

Procedure:
A mixture of 32.5 g (0.25 mol) of 6-methylindole and 52.5 g (0.30 mol) of α-nitro-β-ethoxyacrylic acid methylester was let stand in a large crystallization dish at room temperature for 20 hours. The brown-orange solid was triturated with ether-hexane 1:1, the crystalline material collected by filtration, washed with ether and dried to afford 44.5 g. (69%) of product as orange crystals, m.p. 167- 169°.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([O:15][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH3:14])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(O)c1ccc(C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ncnc2ccccc12)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a mixture of 0.5 g of sodium hydride in 100 ml of DMF was added 2.0 g of 1-[4-(t-butyl)phenyl]ethanol, and the resulting mixture was stirred at room temperature for one hour. Then 1.8 g of 4-chloroquinazoline in 30 ml of DMF were added. The mixture was stirred at room temperature for three hours, then poured into an ice/water mixture. The product was extracted into ether, the ether solution was concentrated and the residue was recrystallized from a pentane/ethyl acetate mixture to give 0.300 g of the title product. M.P. 85°-86° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C:19]([CH3:27])([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:20]#[N:21]>>[CH3:26][S:23]([CH2:22][C:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([O:11][C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:27])[C:20]#[N:21])(=[O:25])=[O:24]
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1Br)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)CS(C)(=O)=O)ncc1Br)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 96d) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting materials and isolated (690 mg, 50%) as a yellow oil; MS (ESI, m/z): 458.3 (M+H+).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C[O-].[Na+].[NH2:26][NH:27][C:28](=O)[CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)C.CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:28]([CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[NH:27][N:26]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)CN1CCOCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Fc1ccc(-c2n[nH]c3ccc(-c4n[nH]c(CN5CCOCC5)n4)cc23)cc1
Temperature: 0 °C
Yield: 5 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.300 g, 0.94 mmol) in 4 mL of anhydrous ethanol was prepared and cooled to 0° C. An excess of a freshly prepared solution of sodium methoxide in methanol (1.41 mL, 2.0 M)) was added followed by 3 equivalents of N-amino-2-morpholin-4-ylacetamide (0.449 g, 2.82 mmol) as a solid. The reaction mixture was heated to reflux temperature in a sealed tube for 2 days. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The components of the crude mixture were separated by preparative HPLC (title compound: 0.017 g, 5% yield): 1H NMR (CD3OD) δ 8.71 (d, 1H), 8.08–8.03 (m, 3H), 7.68 (d, 1H), 7.3 (t, 2H), 3.73 (m, 6H), 2.59 (m, 4H); ES-MS (m/z) 379 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:9])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of oxane-4-carboxylic acid (45 mg, 0.34 mmol), HATU (162 mg, 0.43 mmol) and DIPEA (43 μl, 0.25 mmol) in DMF (1 ml) is stirred at RT for 30 minutes. Tert-butyl-N-[5-amino-6-(2-phenylethynyl)pyridin-2-yl]carbamate B5a (60 mg, 0.19 mmol) is added and stirring continued for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 40 mg (49%). HPLC-MS: M+H=422; tR=1.73 min (*Method—5).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>[OH-].[Na+].C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Temperature: 50 °C
Yield: 8.4 %

Procedure:
D3 (38 mg) was dissolved in 2M aqueous NaOH (0.5 ml) and MeOH (0.5 ml) then stirred at RT overnight. LCMS analysis showed 41% product so the reaction mixture was heated to 50° C. and stirred over the weekend. LCMS showed the reaction to be complete. The reaction mixture was evaporated then partitioned between H2O and DCM. The organic layer was extracted with H2O. The combined aqueous extracts were acidified to pH=1 and extracted with DCM. These DCM extracts were dried over MgSO4, filtered and evaporated to give the crude product MF105672-149A1 (30 mg). The crude product was purified on a silica cartridge (12+S), eluting with a 0 to 10% mixture of MeOH in DCM to give the purified product. This was dissolved in CHCl3 and evaporated to give the title compound (3 mg) as a white solid. δH (CDCl3, 400 MHz): 2.92 (2H, t), 4.50 (2H, t), 6.51 (1H, d), 7.24 (1H, d), 7.40-7.53 (6H, m), 7.90 (1H, s), 8.00 (1H, d), 8.45 (1H, s). MS (ES+): C24H16F3N3O3S requires 483; found 484 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([O:15][CH3:30])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 3,4-bis((tert-butoxycarbonylamino)methyl)benzoic acid (380 mg, 1 mmol) in THF (5 mL) was added NaH (200 mg, 60%). After stirring at room temperature for 20 min, MeI (4 eq) was added and the resultant solution stirred at room temperature overnight. Water was added and the aqueous phase extracted with EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to afford methyl 3,4-bis((tert-butoxycarbonylamino)methyl)benzoate (368 mg). The ester was hydrolyzed following the procedure described in step 1e of Example 14 to afford 3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1CBr
Yield: 14.7 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-thiazol-2-ylmethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (0.551 g, 1.61 mmol), N-bromosuccinimide (0.315 g, 1.77 mmol), and benzoyl peroxide (39 mg, 0.161 mmol) in CCl4 (20 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-60% EtOAc/hexanes) to give 100 mg of the title compound as a orange viscous oil. MS: (+) m/z 423.03 (M+1).