Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:37][C@@H:36]3[CH2:38][C@H:33]2[CH2:34][N:35]3[CH3:39])[N:3]=1>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:37][C@@H:36]3[CH2:38][C@H:33]2[CH2:34][N:35]3[CH3:39])[N:3]=1
Reactant: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Solvent: CO
Product: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Yield: 49.7 %

Procedure:
[(2R)-3-(2-{2-chloro-5-fluoro-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (90 mg, 0.18 mmol) was dissolved in 3 mL of MeOH, degassed and placed under argon. 10% Pd/C (18 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 3 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. The resulting filtrate was concentrated in vacuo to provide the pure [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (42 mg, 57%). LCMS: (M+H)+: 429.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A solution of indole (5.6 g 48 mmol,) in DMF at 0° C. was treated with sodium hydride (1.84 g, 48 mmol), stirred for 10 minutes at room temperature, treated with methyl 4-(bromomethyl)benzoate (10 g, 44 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 30%) to give the title product in 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 266 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)=[O:16]>>[CH:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: Nc1ccncc1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)Nc2ccncc2)cc1
Yield: 55.6 %

Procedure:
In the same manner as that described in Example 1(1), a reaction was carried out using commercially available 4-aminopyridine (159 mg, 1.7 mmol), triethylamine (0.38 ml, 2.7 mmol) and 4-formylbenzoyl chloride (400 mg, 2.4 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 1(1) to afford a crystalline residue which was recrystallized from a mixture of tetrahydrofuran and hexane to give 4-formyl-N-(4-pyridyl)benzamide (214 mg, yield 56%) as white powdery crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[S:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][O:37][CH3:38])[CH2:30][C:29]=3[CH:39]=2)[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[S:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][O:37][CH3:38])[CH2:30][C:29]=3[CH:39]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCSc2ccc(Nc3nc(Cl)ncc3Cl)cc2C1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)CN(CCOC)CCS5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-yl]-amine in an analogous manner to example 730. Product was isolated as a tan solid (0.040 g, 42%). Mp 62-66° C. LCMS (m/e) 568 (M); 1H-NMR (DMSO, 400 MHz) δ 9.17 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.62-57 (m, 2H,), 7.41-39 (d, 1H, J=8.85 Hz), 7.13-08 (m, 2H), 6.95-89 (d, 1H, J=8.34 Hz), 3.99 (s, 2H), 3.65-55 (s, 2H), 3.48-3.40 (q, 1H, J=5.79 Hz), 3.38-32 (t, 2H, J=5.56 Hz), 3.28-20 (m, 2H), 2.95-85 (m, 6H), 2.82-62 (m, 6H), 2.49-43 (t, 2H, J=5.81 Hz), 2.43-35 (m, 2H), 1.10-0.98 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH:32]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([N:45]1[CH2:50][CH2:49][N:48]([C:22]([C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[O:24])[CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzhydrylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=680.99 (M+H+); retention time=1.00 minutes.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=Cc1ccc(Br)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(Br)s1

Procedure:
In analogy to example 13, step 1, 5-bromothiophene-2-carboxaldehyde was reacted with isobutylamine and sodium borohydride in methanol to give (5-bromo-thiophen-2-ylmethyl)-isobutyl-amine as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21](=O)[CH3:22].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:28][O:27][C:25]([CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:22])=[C:13]([Cl:12])[CH:14]=1)=[O:26]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Yield: 9.7 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.15 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 10.3 g of methyl 3-chloro-4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 19), 200 ml of benzene, 100 ml of absolute methanol and 6 g of sodium cyanoborohydride, 1.2 g of the title compound were obtained as crystals, melting at 83°-103° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: OC1C=C2C(C=C(C(O)=O)C=N2)=CC=1.C[O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]=[N:24]2)=[CH:19][CH:18]=1>Br>[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]=[N:24]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: Br
Agent: O=C(O)c1cnc2cc(O)ccc2c1
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Temperature: 105 °C
Yield: 78.7 %

Procedure:
7-Hydroxyquinoline-3-carboxylic acid. Ethyl 7-methoxyquinoline-3-carboxylate (7.03 g, 30.4 mmol) was dissolved in HBr (48% aq., 150 mL) and was heated at 105° C. for 88.5 h. The reaction was cooled to ambient temperature and the precipitate was collected by filtration to afford the title compound as a brown solid (5.2 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.05-11.67 (m, 1H), 9.49 (d, J=2.0 Hz, 1H), 9.43 (s, 1H), 8.39 (d, J=9.8 Hz, 1H), 7.55-7.51 (m, 2H). [M+H]=190.2.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]2[N:14]=[C:13]([CH2:15]Cl)[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:21][OH:22]>>[N:3]1([C:9]2[N:14]=[C:13]([CH2:15][O:22][CH3:21])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cnc(N2CCCCC2)nc1CCl
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COCc1nc(N2CCCCC2)ncc1C(=O)OC
Reaction time: 3 h
Yield: 44 %

Procedure:
Sodium hydride (0.19 g; 7.8 mmoles) was added to 50 ml of methanol, and 2.1 g (7.8 mmoles) of 2-piperidino-4-chloromethyl-5-methoxycarbonylpyrimidine was added at room temperature. The mixture was stirred for 3 hours. After the solvent was evaporated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.90 g (yield 44%) of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH2:14][Cl:18])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2cccc(Br)c2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2cccc(Br)c2)nc1CCl
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A solution of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then stirred at reflux for 30 min. The reaction was then cooled to room temperature and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(3-bromophenyl)-4-(chloromethyl)-5-methyloxazole as a lime-green powder. 1H NMR (300 MHz, d6-DMSO) δ 8.19 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 4.45 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:20][C:21]1([CH3:29])[O:25][C@@H:24]([CH2:26][O:27][NH2:28])[CH2:23][O:22]1>>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:28][O:27][CH2:26][C@H:24]1[CH2:23][O:22][C:21]([CH3:29])([CH3:20])[O:25]1)=[O:7]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccnc(Cl)c1Nc1ccc(I)cc1F
Product: CC1(C)OC[C@H](CONC(=O)c2ccnc(Cl)c2Nc2ccc(I)cc2F)O1

Procedure:
2-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 2-chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid and 0.3 mmol of O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-hydroxylamine LC/MS [9.19 min; 522 (M+1)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])(C)(C)C.CCCCC.[B:19](OC)([O:22]C)[O:20]C>O1CCCC1>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:20][BH:19][OH:22]
Reactant: Cc1ccccc1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1OBO

Procedure:
Following General Procedure A and using 2-bromotoluene (2 g, 7.8 mmol), 20 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (14 mL, 15.5 mmol) and trimethyl borate (2.6 mL, 15.5 mmol), the title compound was obtained after recrystallization from ethyl acetate-hexane mixture (0.8 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:17](=[O:18])[CH:12]3[CH2:13][S:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[C:21]1=[O:36].I([O-])(=O)(=O)=[O:38].[Na+].CCOCC>CO.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:17](=[O:18])[CH:12]3[CH2:13][S:14](=[O:38])[CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([O:32][CH:33]([CH3:34])[CH3:35])=[O:31])[C:21]1=[O:36]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N3C(=O)C4CSCCN4C3=O)c(F)cc2Cl)c1=O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N3C(=O)C4CS(=O)CCN4C3=O)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of isopropyl 3-{2-chloro-4-fluoro-5-[5,6,8,8a-tetrahydro-1,3-dioxo-1H-imidazo[5,1-c][1,4]thiazin-2(3H)-yl]phenyl}tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.95 g, 1.75 mmol) in methanol (10 mL) is added over 15 minutes to a solution of sodium periodate (0.38 g, 1.78 mmol) in water (10 mL) which is previously cooled to 0°-5° C. After the addition is complete, the reaction mixture is stirred at room temperature overnight, diluted with methylene chloride, washed sequentially with a one molar KH2PO4 solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow foam. Flash column chromatography of the foam using silica gel, a 10% ether in methylene chloride solution and a 2.5% methanol in methylene chloride solution gives the title product as a white foam (0.59 g, mp 175°-180° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[CH2:28][N:27](C(=O)C)[CH2:26][C:25](=[O:32])[N:24]([CH2:33][CH3:34])[C:23]=3[CH:35]=2)[N:12]=1)=[O:4].C(Cl)Cl.CO>CN.O.CN.C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[CH2:28][NH:27][CH2:26][C:25](=[O:32])[N:24]([CH2:33][CH3:34])[C:23]=3[CH:35]=2)[N:12]=1)=[O:4]
Reactant: CCN1C(=O)CN(C(C)=O)Cc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Agent: CN
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1C(=O)CNCc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Yield: 30.4 %

Procedure:
A solution of 3-[2-(4-acetyl-1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (157 mg, 0.3 mmol) in 12 mL of 40% methylamine/water and 3 mL of 2M methylamine/THF) was heated in a sealed tube at 120° C. for 16 hours. Chromatography of the concentrated residue on TLC plates with methylene chloride and methanol (100:9) gave 43 mg of 3-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (29%): 1H NMR (300 MHz, CD3OD) δ 8.42 (d, 1H), 8.1 (s, 1H), 7.88 (s, 1H), 7.45 (m, 2H), 7.33 (d, 1H), 3.92 (m, 4H), 3.35 (s, 2H), 2.9 (s, 3H), 1.18 (t, 3H); MS (m/e): 472.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:36])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:6]([CH3:36])=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][C:8]=3[CH3:10])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless foam. MS: m/e=503.2 [M+H+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(Cl)Cl.OS(O)(=O)=O.[Br:22]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:22][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portion over 7 hours. The reaction mixture was stirred for 4 days at room temperature, poured into ice-water and extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:13][CH:14]([O:24]C1CCCCO1)[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=[O:5])[CH3:2].C[Si](C)(C)Br.C>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]([CH2:13][CH:14]([OH:24])[CH2:15][P:16](=[O:17])([OH:23])[OH:20])[OH:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N(O)CC(O)CP(=O)(O)O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (5.01 g.) in methylene chloride (10 ml.), was added dropwise trimethylbromosilane (6.73 g.) with stirring under ice-cooling. The mixture was stirred for an hour under ice-cooling and for additional 2 hours at ambient temperature and evaporated under reduced pressure to remove off the solvent and unreacted excess trimethylbromosilane. The residue was dissolved in water (50 ml.), stirred for an hour at ambient temperature and washed twice with chloroform (20 ml. and 10 ml. portions). The combined chloroform washings were extracted with water (30 ml.). The aqueous extract was washed once again with chloroform (5 ml.) and combined with the above-remained aqueous solution and then evaporated to dryness under reduced pressure to give a tarry residue. This residue was dissolved in water (40 ml.) treated with an activated charcoal (300 mg.) and evaporated to dryness under reduced pressure to give oily 3-(N-ethoxycarbonyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (2.6 g.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CN1CCN(c2cc(Sc3ccc(Cl)cc3)nc(-c3ccccc3)n2)CC1
Temperature: 160 °C

Procedure:
A well blended mixture of the above prepared 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine (2.0 g.) and 5.0 g. of p-chlorothiophenol is heated in an oil bath maintaining the temperature at 160°C. for 3 hours. After being cooled to room temperature, the reaction mixture is triturated with 60 ml. of 30°/o sodium hydroxide. The product is collected on a sintered glass funnel and washed with water repeatedly. It amounted to 2.9 g. and melted at 145°-150°C. Upon recrystallization from absolute ethanol, there is obtained 4-(4-chlorophenylthio)-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine, m.p. 152°-154°C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:31])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:31])=[CH:16][CH:17]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)cc1

Procedure:
2-(2′-Methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 1.7 mmol) was dissolved in 25 mL DCM and 5 mL trifluoroacetic acid and stirred at ambient temperature for one hour and concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated to yield title compound as an oil (quant. yield) APCI (AP−): 343.1 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[CH3:2].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N(CC(O)=O)C=1)(=O)C>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2ccccc12
Agent: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1nn(CC(=O)O)c2ccccc12

Procedure:
The title compound was prepared from tert-butyl 2-(3-acetyl-1H-indazol-1-yl)acetate in a similar manner as described in step C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 219 [M+H]+; tR (HPLC conditions k): 2.78 min.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C1(N=C=NC2CCCCC2)CCCCC1.C(O)C1C=CC=CC=1>O1CCCC1>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3]
Reactant: O=C(O)C[C@@H](O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)CC(O)C(=O)O

Procedure:
In an example of the process wherein the cyclic anhydride is formed with a diimide, D-malic acid is dissolved in tetrahydrofuran and 1.1 molar equivalents of dicyclohexylcarbodiimide are added to the solution. The reaction mixture is stirred for about an hour and is then filtered to remove the precipitate of dicyclohexylurea. An excess (ca. 1.5 to 2.0 equiv.) of benzyl alcohol is added to the filtrate containing the malic acid cyclic anhydride and the solution is stirred for about 6 to about 12 hours. The reaction mixture is evaporated and the impure monobenzyl malate is dissolved in a water immiscible solvent such as ethyl acetate. The product is extracted with a base such as aqueous sodium bicarbonate, and after acidification of the extract the ester is extracted with ethyl acetate or other suitable solvent. The extract is dried and evaporated to yield the monobenzyl ester of malic acid represented by the formula ##STR51##