Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[S:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[S:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)c(F)c2)OC1(C)C
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5nc6ccccc6s5)c(F)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzothiazol-2-amine was prepared from trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine (0.105 g, 0.283 mmol) in a manner similar to that used for the cis-isomer. The compound was formed as a white powder (0.052 g, 41%):
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18]CC)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[N:25]2[CH2:28][C:27]([F:30])([F:29])[CH2:26]2)[CH2:3][CH2:2]1.[OH-].[Li+]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([OH:18])=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[N:25]2[CH2:28][C:27]([F:29])([F:30])[CH2:26]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O

Procedure:
In analogy to the procedure described in Example 5 c), (S)-ethyl 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-4-methylpentanoate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e=396.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:28][CH2:29][CH2:30][CH3:31])[C:3]([NH:5][CH2:6][C@H:7]1[O:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:8]1[CH2:21][C@H:22]([CH2:26][OH:27])[CH:23]([CH3:25])[CH3:24])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:32][C:2]([CH3:1])([CH2:28][CH2:29][CH2:30][CH3:31])[C:3]([NH:5][CH2:6][C@H:7]1[O:11][C:10]([CH3:12])([CH3:13])[N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:8]1[CH2:21][C@H:22]([CH:26]=[O:27])[CH:23]([CH3:24])[CH3:25])=[O:4]
Reactant: CCCCC(C)(C)C(=O)NC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](CO)C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C=O)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (4S,5R)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxymethyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (100 mg, 0.22 mmol) in anhydrous CH2Cl2 (5 mL) was added Dess-Martin reagent (120 mg, 0.283 mmol). The reaction mixture was stirred at rt for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to (4S,5R)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (80 mg, 80%), which was used without purification; MS: 455 (M++1).
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[CH3:43][O:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[CH3:43][O:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:36]2[C:37]3[N:38]([N:39]=[CH:40][N:41]=3)[C:33]([Br:32])=[CH:34][N:35]=2)=[CH:48][CH:47]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (250 mg, 0.90 mmol), 4-aminobenzoic methyl ester (163 mg, 1.08 mmol) and N-ethyldiisopropyl-amine (0.19 mL, 1.08 mmol) in 2-propanol (2.5 mL). The title compound is obtained after trituration with 2-propanol as a brown solid (148 mg, 47%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:31][C:32]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35]>C(Cl)Cl.CN1CCOCC1.CC(O)=O>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:20]2[O:22][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[C:32]=3[N:31]=2)=[CH:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
Using the procedure of Step A of Example 7, a solution of 22.8 g of BOC-L-Tryptophane in 150 ml of methylene chloride and 20.6 g of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride, 15.4 g of 2-amino-3-trifluoromethyl benzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted to obtain 20.7 g of 1,1-dimethylethyl N-[(S) 2-[1H-indol-3-yl]-1-[4-oxo-8-trifluoromethyl-4H-3,1-benzoxazin-2-yl]-ethyl-carbamate melting at 166° C. and having a specific rotation of [α]D =-52°±2.5° (c=0.4% in CH3COOH).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:47][CH2:46][CH2:45][CH2:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCCCc1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCCc4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3-phenylpropylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 87% yield, m.p. 191° C. MS [(+)ESI, m/z]: 570 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[NH:33][C:29]3[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(F)cc5)nc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added 3-methylphenylisocyanate (0.15 mmol). The reaction was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (28 mg) which was characterized by its mass spectrum: MS m/z (%): 492 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C(O)CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[NH:48][N:47]=[N:46][N:25]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCC#N)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCc4nnn[nH]4)c23)cc1
Reaction time: 1 h

Procedure:
Stir 1.00 g (2.1 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}hexanenitrile, 0.79 g (3.2 mmol) di-n-butyltin oxide and 3.68 g (32 mmol) trimethylsilylazide in 44 ml toluene overnight at 80° C. Then add 1 ml ethylene glycol, stir for 1 h under reflux and then concentrate by evaporation. Take up the residue in ethyl acetate, wash with dilute hydrochloric acid and with sodium chloride solution, dry, and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). Crystallize the combined product fractions from diethyl ether. 372 mg (38% of theor.) of the title compound is obtained as beige crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=[C:17]([N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=3[N:29]=[C:28]2[CH:38]([F:40])[F:39])[N:16]=1>C1COCC1.C(O)(=O)C.O>[F:40][CH:38]([F:39])[C:28]1[N:27]([C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([NH:1][C:2]3[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=3)[N:16]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=2[N:29]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2ccc(F)nc2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To 0.240 g (2.14 mmol) of 5-amino-2-fluoropyridine in THF (5 mL) was added 0.94 mL of n-butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 10 min. A solution of 0.283 g (0.71 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent followed by chromatography on alumina eluting first with hexanes/EtOAc (1:1) and then CH2Cl2/EtOAc (1:3) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.135 g (40% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-fluoro-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 261-263° C.; 1H NMR (CDCl3) δ8.44 (br s, 1H), 8.03-8.01 (m, 1H), 7.90 (br s, 1H), 7.61-7.31 (m, 2H), 7.07 (br s, 1H), 6.99 (dd, J=8.3, 3.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.93-3.88 (m, 4H), 3.80 (s, 4H); Anal. Calcd. for C21H19F3N8O2: C, 53.4; H, 4.05; N, 23.7. Found: C, 53.5; H, 4.0; N, 23.8%.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]1[CH2:8][CH2:7][N:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])[CH2:5][CH2:4]1.O.[OH-].[Li+].O>CO>[F:27][C:2]([F:1])([F:26])[CH:3]1[CH2:8][CH2:7][N:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:13]2=3)(=[O:10])=[O:11])[CH2:5][CH2:4]1
Reactant: COC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCC(C(F)(F)F)CC1)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2c(c1)N(S(=O)(=O)N1CCC(C(F)(F)F)CC1)CCO2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 1-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (0.280 g, 0.684 mmol) in MeOH (20 mL) was added lithium hydroxide monohydrate (0.144 g, 3.42 mmol) and water (4.00 mL) which provided a white suspension. The reaction was stirred at room temp for 2.5 h. The MeOH was removed under reduced pressure and the resulting aqueous solution was neutralized with concentrated HCl (400 mL) to provide a white solid. The suspension was extracted EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to provide 1-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid as a white solid. The yield was assumed to be 100% for calculation purposes in subsequent reactions. LCMS (+ESI) m/z=396.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl.O>[F:22][C:12]([F:11])([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH:13]=[O:14]
Reactant: OCC(F)(F)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: O=CC(F)(F)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A stirring solution of 7.0 grams (0.055 mole) of oxalyl chloride in 125 mL of methylene chloride is cooled to -60° C., and a solution of 9.5 grams (0.120 mole) of dimethyl sulfoxide in 25 mL of methylene chloride is added dropwise during a five minute period. Upon completion of addition, the reaction mixture is stirred at -60° C. for about 10 minutes, and then a solution of 9.6 grams (0.050 mole) of 2,2-difluoro-2-(4-chlorophenyl)ethanol in 25 mL of methylene chloride is added dropwise during a five minute period. Upon completion of addition, the reaction mixture is stirred for 15 minutes, and 25.5 grams (0.250 mole) of triethylamine is added while maintaining the reaction mixture temperature at -60° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature, and 150 mL of water is added. The mixture is stirred for 10 minutes, and the organic layer is separated. The aqueous layer is washed with 100 mL of methylene chloride. The methylene chloride wash and the organic layer are combined, and the combination is washed with 100 mL of water and then with 100 mL of an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding difluoro-4-chlorophenylacetaldehyde.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH:16]2[CH2:21][NH:20][CH2:19][C:18]3[CH:22]=[CH:23][S:24][C:17]2=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:20]1[CH2:21][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]2[S:24][CH:23]=[CH:22][C:18]=2[CH2:19]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: c1ccc(C2CNCc3ccsc32)cc1
Product: c1ccc(CCN2Cc3ccsc3C(c3ccccc3)C2)cc1

Procedure:
Phenethyl bromide is condensed with 7-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Example 4) according to the procedure of Example 8.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24](=[O:37])[NH:25][C:26]3[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=3[O:35][CH3:36])[C:13]2=[O:38])=[CH:8][CH:7]=1)C.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:32][C:30]1[C:29]([O:33][CH3:34])=[CH:28][C:27]([O:35][CH3:36])=[C:26]([NH:25][C:24]([CH2:23][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:39])=[O:3])=[CH:7][CH:8]=3)[C:13]2=[O:38])=[O:37])[CH:31]=1
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)c(OC)cc3OC)c2=O)cc1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(-c3ccc(CC(=O)O)cc3)c(=O)c3ccccc32)cc1Cl
Temperature: 120 °C

Procedure:
(4-[1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-phenyl)-acetic acid ethyl ester (Intermediate K) (105.4 mg, 0.19 mmol) is added to a stirred solution of Bis(tributyltin)oxide) (2 eq, 0.38 mmol, 193.1 μL) in toluene (10 ml). The mixture is heated at reflux at 120° C. for 72 hours. The toluene is removed in vacuo, and the red/brown oily residue is partitioned between EtOAc and saturated NaHCO3 (5 ml). The resultant precipitate is filtered, washed with NaHCO3, EtOAc, 1M HCl, water, and dried to give the title compound, [M+H]+ 524
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH:10]=[C:9]([O:13][CH2:14][C:15]([O:17]C)=[O:16])[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH:10]=[C:9]([O:13][CH2:14][C:15]([OH:17])=[O:16])[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)COc1coc2c(OC)cccc2c1=O
Agent: Cl
Product: COc1cccc2c(=O)c(OCC(=O)O)coc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of methyl [(8-methoxy-4-oxo-4H-1-benzopyran-3-yl)oxy]acetate (200 mg) in 6N hydrochloric acid (20 ml) is stirred at 100° C. for 3 hrs. under nitrogen. The reaction is cooled and the product filtered off and sucked dry. Recrystallization from methanol gives white crystals (180 mg. 86%), mp 215°-217° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCl.C(O)(=O)C.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]([N+:6]([O-:9])=[O:7])=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCCN2CCOCC2)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 161.8 %

Procedure:
Concentrated sulphuric acid (110 ml) and concentrated nitric acid (19.0 ml, 0.289 mol) were added cautiously, over a 50 minute period, to a two-phase system containing a stirred solution of ethyl 3-methoxy-4-(3-morpholinopropoxy)benzoate (76.5 g, 0.237 mol) in dichloromethane (600 ml), acetic acid (300 ml) and water (70 ml) at 5° C. The reaction was allowed to warm to ambient temperature over 18 hours, the aqueous phase was separated, and the aqueous phase was taken to pH 9 by addition of 40% aqueous sodium hydroxide solution (775 ml). Extraction of the aqueous phase with dichloromethane (3×600 ml) and subsequent solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-nitrobenzoate (141.3 g, 86% yield) as a yellow gum:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([NH:23][C:24](=[O:44])[CH2:25][NH:26][C:27](=[O:43])[C:28]2[CH:33]=[C:32]([NH:34][C:35]3[NH:36][CH2:37][CH:38]([OH:41])[CH2:39][N:40]=3)[CH:31]=[C:30]([OH:42])[CH:29]=2)[CH2:17][C:18]([O:20]CC)=[O:19])[CH:5]=[C:6]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([NH:23][C:24](=[O:44])[CH2:25][NH:26][C:27](=[O:43])[C:28]2[CH:33]=[C:32]([NH:34][C:35]3[NH:40][CH2:39][CH:38]([OH:41])[CH2:37][N:36]=3)[CH:31]=[C:30]([OH:42])[CH:29]=2)[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[C:6]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: N#CC1(c2cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c3cc(O)cc(NC4=NCC(O)CN4)c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.842 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (180.0 mg, 4.289 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The aqueous layer was separated and acidified with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale orange viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized powder (305 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 599 (35ClM+H) and m/z 601 (37ClM+H); Calcd for C28H31ClN6O7:599.03.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[CH3:19])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(Cl)Cl.B(Br)(Br)[Br:32].C([O-])(O)=O.[Na+]>C(=O)=O>[Br:32][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][C@@H:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH3:19])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc([C@@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](Nc1nc(Nc2cccc(CBr)c2)ncc1Cl)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Into a 1-neck round-bottom flask were added {3-[(5-chloro-4-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.26 g, 0.68 mmol) and methylene chloride (5 mL). To the mixture was added a solution of boron tribromide in methylene chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in dry ice when NaHCO3 (saturated aqueous solution, 10 mL) was added. The mixture was allowed to warm up to rt and DCM was added. The aqueous layer was extracted with DCM twice. The organic layers were combined, dried, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product (40 mg, 30%). LCMS for C19H19BrClN4O (M+H)+: m/z=432.9, 434.9.