Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 25.0 g of 3,5-dichlorophenyl boronic acid in 200 mL of tetrahydrofuran and 100 mL of water, 27.5 g of 2-bromo-3,3,3-trifluoropropene, 38.0 g of potassium carbonate and 1.84 g of dichlorobis(triphenylphosphine) palladium (II) were added, and the resultant reaction mixture was stirred while heating the mixture to reflux for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 500 mL of ice water was added to the reaction mixture, followed by extracting the reaction mixture with ethyl acetate (500 mL×1). Subsequently, the organic phase was washed with water and was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 25.7 g of the objective substance as a colorless oily substance.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)[C:5]#[N:6].O.[NH2:17]N>C(O)C>[CH3:13][C:11]1[CH:12]=[C:7]([C:4]2[CH:5]=[N:6][NH:2][C:3]=2[NH2:17])[CH:8]=[C:9]([CH3:14])[N:10]=1
Reactant: Cc1cc(C(C#N)=CN(C)C)cc(C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cn[nH]c2N)cc(C)n1
Yield: 39 %

Procedure:
To stirred solution of 3-dimethylamino-2-(2,6-dimethyl-pyridin-4-yl)-acrylonitrile (2.2 g, 10.9 mmol) in ethanol (22 ml) was added at room temperature hydrazine monohydrate (1.17 ml, 24.1 mmol), the reaction mixture was heated under reflux conditions for 23 h and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH4OH 80:10:1) and crystallization from diethyl ether yielded 4-(2,6-dimethyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.8 g, 39%) as a light brown solid. MS (ISP) 189.3 [(M+H)+]; mp 222° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:16]=O)[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]([NH2:24])([CH2:22][OH:23])[CH2:20][OH:21]>CCO.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:7]([CH2:16][NH:24][C:19]([CH3:18])([CH2:22][OH:23])[CH2:20][OH:21])[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:15]=1
Reactant: O=Cc1c2ccccc2cc2c(Cl)cccc12
Reactant: CC(N)(CO)CO
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccccc2cc2ccc(Cl)cc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 4-chloro-9-anthracenecarbaldehyde and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave 2-((2-chloro-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride, mp 225°-226° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9]O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: ON=Cc1c(Cl)ncnc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Cl)ncnc1Cl

Procedure:
4,6-Dichloro-5-pyrimidinecarbaldehyde oxime (8 g) was dissolved in CHCl3 (40 mL) and treated with SOCl2 (6 mL) for 2 h at rt. The solvent was removed and the residue was dissolved in DCM (5 mL). The resulting solid was filtered and washed with DCM (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using DCM-hexane (3:1) to give 4,6-dichloro-5-pyrimidinecarbonitrile as a white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[OH:9][C:10]([CH3:48])([CH3:47])[CH2:11][O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]3[N:44]=[N:45][CH:46]=[C:20]23)[CH2:15][CH2:14]1>CS(C)=O.C(OCC)(=O)C>[OH:9][C:10]([CH3:47])([CH3:48])[CH2:11][O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:3][C:4](=[O:7])[O:5][N:40]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]3[N:44]=[N:45][CH:46]=[C:20]23)[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2cnnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2cnnn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (292 mg), sodium hydrogen carbonate (470 mg) and dimethyl sulfoxide (2 mL) was stirred at 60° C. for 30 min, a solution of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (153 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (55 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (52 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→30/70 (volume ratio)] to give the title compound as a colorless amorphous compound (68 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=O)[C:6]=2[CH:18]=1.[B].CSC.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][C:6]=2[CH:18]=1
Reactant: O=c1[nH]c2ccccc2c(=O)c2cc(Cl)ccc12
Agent: [B]
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)Cc1ccccc1NC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a mixture of 7.28 g of 9-chloro-5H-dibenz-[b,e]azepin-6,11-dione in 25 ml of tetrahydrofuran under argon is added 8.5 ml of 10 molar boron-dimethyl-sulfide in tetrahydrofuran. The mixture is stirred 18 hours at room temperature, 30 ml of tetrahydrofuran added and the mixture refluxed for 3 hours (solids dissolved). The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2N NaOH. The mixture is refluxed overnight and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed to give 4.2 g of solid which is triturated with ethyl acetate-hexane (1:2) to give crystals, m.p. 137° C. to 141° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 127–129° C.; 1H NMR (300 MHz, CDCl3): δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 4.11–4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94–1.74 (m, 2 H), 1.07–0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80–0.73 (m, 1 H), 0.55–0.44 (m, 2 H), 0.34–0.25 (m, 1 H); HRMS (ESI) calcd for C19H21N3O2Cl2F (M+H)+: 412.0995; found m/z 412.1001.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>>[NH2:2][C:1]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[N:26]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2nn(-c3ccc(Br)cc3)c(N)c2C(N)=O)cc1
Yield: 31.7 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (928 mg, 4.0 mmol), 4-bromophenylhydrazine hydrochloride (894 mg, 4.0 mmol) and sodium hydroxide (176 mg, 4.4 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 10% methanol in CH2Cl2) and recrystallisation from ethyl acetate to give the title compound as white crystals (470 mg) m.p. 222-223°. δH (CDCl3) 7.63 (2H, dt, J 8.8, 2.2 Hz), 7.52 (2H, dt, J 8.5, 2.6 Hz), 7.48 (2H, d, J 7.4 Hz), 7.28 (2H, d, J 8.3 Hz), 5.74 (2H, br s), 5.29 (2H, br s), 2.41 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:18][CH:17]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1nc(OCCO)c(-c2ccc(Cl)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc(Cl)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (21 mg) of 5-bromo-2-chloropyrimidine was used and 4-(tert-butyl)-N-[4-(4-chlorophenyl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]benzenesulfonamide (Example 19) (30 mg) was used in place of 4-(tert-butyl)-N-(3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (3 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:13]=[N:14][N:15]=[C:7]1[CH:6]=[CH:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc2cc(Br)ccc2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(ccc3nnnn32)c1
Temperature: 130 °C

Procedure:
To 6-Bromo-2-chloro-quinoline (223 mg, 1.0 mmol) in DMF (10 mL) was added sodium azide (65 mg, 1.0 mmol). The reaction was heated at 130° C. for 1 hour, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 9d.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CNc1ccc(Oc2ccccc2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h

Procedure:
N-(4-Phenoxyphenyl)glycine methylester (Intermediate 75, 13.5 g, 0.0525 mol) was dissolved in a mixture of acetic acid (90 ml) and water (5 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (3,8 g, 0.55 mol) in water (10 ml) over 15 minutes. Stirring was continued for 2 hours and the reaction was cooled to ~0° C. Zinc dust (13.4 g, 0.2048 mol) was added over 30 minutes and the reaction stirred at 0°-5° C. for 2 hours before being poured into water (200 ml) and extracted with ethyl acetate (2×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:1) to recover starting material (6.5 g, 48%). The liquors were evaporated and purified by flash column chromatography on silica (Merck 9385; 250 g) eluting with ether-hexane (1:1) to give the title compound (Intermediate 76) as an off white solid (1.25 g, 9%) m.p 71°-73° C.
Reaction SMILES: [CH:1]1([Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1(O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>C[O-].[Na+]>[CH:10]1([O:9][Si:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([O:11][CH3:12])[O:7][CH3:8])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]1
Reactant: CO[Si](OC)(OC)C1CCCC1
Reactant: OC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Product: CO[Si](OC)(OC1CCCCC1)C1CCCC1
Yield: 83.3 %

Procedure:
The procedures of Example 2 were repeated with the exception that 10.0 g (0.0526 mole) of cyclopentyl trimethoxysilane, 85.1 mg (1.58 m mole) of sodium methoxide, and 52.7 g (0.526 mole) of cyclohexanol in place of sec-butyl alcohol were used and the reaction time was one and a half hours. Then, 11.3 g (0.0438 mole) of cyclohexyloxy cyclopentyl dimethoxysilane were obtained. Its structure was confirmed as in Example 1. FIGS. 3 and 4 are the charts of 1H-NMR and IR, respectively. The yield was 83%.
Reaction SMILES: C([Li])CCC.BrC1C=[CH:11][C:10]([F:13])=[CH:9][C:8]=1OC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:30]([O:32][CH2:33][CH3:34])C>>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:34][C:33]=2[O:32][CH3:30])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(F)ccc1Br
Agent: [Li]CCCC
Product: COc1ccc(F)cc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 9.8 mL (24 mmole) butyllithium (2.5M solution in hexane) in diethylether (20 mL) under N2 at −78° C. was slowly added 2-bromo-5-fluoroanisole (5.0 g, 24 mmole) in diethylether (5 mL). The mixture was allowed to warm up to −50° C. At this point, 1-benzyl-4-piperidone (4.62 g, 24.4 mmole) in diethylether (3 mL) was added. The resulting mixture was allowed to stirred at −50° C. for 30 minutes, and then warmed to room temperature. The reaction was quenched by dropwise addition of saturated NH4Cl solution. The mixture was then transferred to a separatory funnel, the layers were separated and the aqueous was extracted three times with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 7:3 EtOAc-hexanes) afforded 5.27 g (68%) of 1-benzyl-4-(5-fluoro-2-methoxy-phenyl)-4-hydroxypiperidine as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.C[CH2:39][N:40](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN1C(=O)CCC1>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:40][CH3:39])=[O:34])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:18][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: CNC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Yield: 76.6 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with methylamine (594 μL, 2M solution. in THF) to give the product as a white solid (118 mg, 77% yield); MS (ESI) m/z=519.3.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:13])[C:3]=1[CH3:14].C(O)C.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O.C(N(CC)CC)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([F:8])=[C:6]([Cl:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:13])[C:3]=2[CH3:14])[CH2:21][CH2:20]1
Reactant: Cc1c(F)c(F)c(Cl)c([N+](=O)[O-])c1F
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(F)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1

Procedure:
To 2,3,6-trifluoro-4-chloro-5-nitrotoluene (0.17 g) are added ethanol (3.3 ml), water (0.5 ml), N-methyl-piperazine (0.45 ml) and triethylamine (0.56 ml) and the mixture is refluxed for 24 hours. After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (eluent; dichloromethane: methanol =20:1) to give 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-chloro-5-nitrotoluene (0.13 g).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](C(O)=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.[C:31](=O)(O)[O-:32].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([N:5]([C:31](=[O:32])[CH:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=[C:15]=[O:22])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)C1C=CC=CC1=C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g), benzoyl formic acid (1 g), and methanesulfonyl chloride (0.7 g) were stirred in toluene (35 ml) and saturated sodium bicarbonate (15 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture, and slowly warmed to room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (20 ml) and the organic layer was washed several times with water. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white gum. The crude product was chromatographed on silica gel (G:230-400 mesh) using a methylene chloride ether solvent system as eluent to afford a 65% yield of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:13])[C@H:10](O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]2([OH:13])[O:48][CH2:47][C:46]([CH3:50])([CH3:49])[NH:45][C@H:10]2[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)[C@@H](C)O)c1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc([C@]2(O)OCC(C)(C)N[C@H]2C)c1
Yield: 72 %

Procedure:
Compound 4f was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-methoxyphenyl)-2-hydroxypropan-1-one (10f, 4.2 g, 0.023 mol), Proton sponge (5.9 g, 0.028 mol), triflic anhydride (4.2 mL, 257 mmol), and 2-amino-2-methyl-1-propanol (4.5 g, 0.051 mol) in CH2Cl2 (50 mL). After purification, 4.16 g (71%) of the free base 4f was isolated and converted to 1.24 g the hemi-D-tartrate salt, which had 91% ee: mp 99-100° C.; [α]20D +7.9° (c 1.1, CH3OH); 1H NMR (methanol-d4) δ 7.32 (t, 1H, J=7.8 Hz), 7.19-7.14 (m, 2H), 6.96-6.92 (m, 1H), 4.33 (s, 1H), 4.18 (d, 1H, J=12.3 Hz), 3.81 (s, 3H), 3.52 (d, 1H, J=12.3 Hz), 3.48-3.45 (m, 1H), 1.59 (s, 3H), 1.34 (s, 3H), 1.06 (d, 3H, J=6.6 Hz). 13C NMR (methanol-d4) δ 178.8, 161.4, 144.1, 130.7, 120.1, 115.4, 113.8, 97.1, 75.2, 67.6, 56.1, 55.2, 24.4, 21.5, 14.5; LCMS (ESI) m/z 252.3 [(M-tartrate)+, % M=C16H24NO6]; Anal. (C16H24NO6.0.5H2O) calcd: C, 57.30; H, 7.51; N, 4.18. found: C, 57.33; H, 7.55; N, 4.14.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]([S:18]([CH3:17])(=[O:20])=[O:19])[S:18]([CH3:17])(=[O:20])=[O:19])[C:7]([I:8])=[CH:6][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Cl)ncc1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(Cl)ncc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 72.9 %

Procedure:
4-Amino-2-chloro-5-iodopyridine (11) (1.01 g, 3.97 mmol) was dissolved in dichloromethane (8.5 mL) and triethylamine (2.48 mL, 1.78 g 17.6 mmol) was added. The suspension was cooled in an ice/water bath. A solution of methanesulfonyl chloride (1.56 mL, 2.31 g, 20.1 mmol) in dichloromethane (4.2 mL) was added dropwise. The reaction was stirred at room temperature for 100 min. More triethylamine (1.25 mL) was added to the reaction, which was then cooled in ice. To the cooled reaction was added dropwise a solution of methanesulfonyl chloride (0.78 mL, 1.15 g, 10 mmol) in dichloromethane (2.1 mL) and stirring at room temperature was continued for 16 h. The reaction was diluted with dichloromethane and washed twice with water. The residue was purified by flash chromatography eluting with dichloromethane, then 5% ethyl acetate in dichloromethane to give the title compound (13) (1.188 g 72%). 1H-NMR (500 MHz, DMSO-d6): 3.69 (s, 6H), 8.03 (s, 1H), 8.99 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:9]([NH:11][C:12]3[CH:13]=[C:14]([CH:18]([NH:22][C:23]4[C:32]5[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:19][CH2:20][OH:21])[CH:15]=[CH:16][CH:17]=3)=[O:10])[NH:7][N:8]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O.[OH-].[Na+]>CS(C)=O.ClCCl>[CH:1]1([C:4]2[CH:5]=[C:6]([C:9]([NH:11][C:12]3[CH:13]=[C:14]([CH:18]([NH:22][C:23]4[C:32]5[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:19][CH:20]=[O:21])[CH:15]=[CH:16][CH:17]=3)=[O:10])[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2c(NC(CCO)c3cccc(NC(=O)c4cc(C5CC5)n[nH]4)c3)ncnc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cccc2c(NC(CC=O)c3cccc(NC(=O)c4cc(C5CC5)n[nH]4)c3)ncnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
227 mg (0.46 mmol) 4-(1-{3-[(5-Cyclopropyl-2H-pyrazole-3-carbonyl)-amino]-phenyl}-3-hydroxy-propylamino)-quinazoline-8-carboxylic acid amide were dissolved in 2.5 ml DMSO and 1.98 ml (0.59 mmol) 0.3 M Dess-Martin Periodane in dichloromethane wee added to the mixture. The mixture was stirred for 2 h at room temperature, 20 ml water and 2 ml 1N NaOH were added and the precipitate was filtered, washed with water and dried in vacuo. 245 mg, off-white solid.