Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1>>[CH3:23][C:24]1[N:25]=[C:26]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:27][CH:28]=1
Reactant: CC(C)(O)c1cccc(Cn2nnc3c(Cl)nc(N)nc32)n1
Reactant: Cc1cscn1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C(C)(C)O)n2)n1

Procedure:
This is prepared from 7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine and 4-methylthiazole by the method of Example 38.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[C:49]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.197 ml of benzoyl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([I:15])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-chloropyridin-3-ol (5.0 g, 38.60 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.37 mmol) was added followed by iodine (9.8 g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into 1 M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H-NMR (CDCl3, 400 MHz) δ 7.17 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H). MS (M+H)+: 256/258.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[Cl:14])C.[O:18]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>>[Cl:14][C:8]1[CH:9]=[C:10]([O:13][CH2:32][CH2:31][CH2:30][O:29][C:28]2[CH:34]=[CH:35][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][CH:27]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH:5]([O:15][CH3:16])[C:4]([OH:3])=[O:17]
Reactant: OCCCOc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1Cl)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1Cl)C(=O)O

Procedure:
A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester from Example 191, Step F and 3-(4-phenoxy-phenoxy)-propan-1-ol were allowed to react under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product which by the Standard hydrolysis procedure C (NaOH) yield the title compound. MS (ES) for C25H25ClO6 [M+NH4]+: 474.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[C:7]([Cl:13])[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)(=O)C.Cl.O>[Br:11][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cc(Cl)c(C)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)c(N)cc1Cl
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A solution of 4-acetamido-5-bromo-2-chlorotoluene (64 g, 0.245 mol) in glacial acetic acid (48 ml) and concentrated hydrochloric acid (96 ml) was heated at 118° C. for 24 h. The reaction mixture was allowed to cool to room temperature, diluted with water (200 ml), cooled in an ice-bath and the pH was. adjusted to 5 with a aqueous solution of NaOH (50% w/v). The precipitate was collected by filtration washed with water, and dried in vacuo over P2O5 to afford a white solid (50.7 g, 94%), mp 90° C.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][C:25](O)=[O:26].CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][C:25](=[O:26])[CH2:24][CH2:23][N:22]([CH3:28])[CH3:21])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCC(=O)O
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)CCC(=O)O/N=C(\N)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by the method of Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], 3-(dimethylamino)propanoic acid [Papapoulos, et al, WO 9619998A1], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-[3-(dimethylamino)propanoyl]oxy-2-piperidinecarboximidamide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:23]=[N:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH:6]=[CH:5]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl>[N:25]1[N:24]=[C:23]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:21])[CH3:22])([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:15])[CH3:16])[CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)[N:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=12
Reactant: CC(C)[Si](Oc1cc(F)cc2ccc(C=NNc3ccccn3)nc12)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)[Si](Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
6-Fluoro-2-((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline (10 g, 23 mmol) was weighed into a 1000 mL 1 neck round bottom flask, followed by addition of iodo benzene diacetate (8.1 g, 25 mmol) and 400 mL of dichloromethane. The mixture was stirred at ambient temperature for 24 hours, at which time the reaction was complete. The crude mixture was partitioned with Na2S2O3, back extracted with DCM, and the combined organics were washed with brine and dried over sodium sulfate, then concentrated in vacuo. The crude product was the purified by flash column chromatography (SP1 Biotage Horizon, 1-15% MeOH/DCM gradient elution), affording the desired product (9.4 g, 94% yield) as a white powder.
Reaction SMILES: [C:1]([O:4][CH:5](C(=O)C)[CH2:6][CH:7]1[C:9]([CH3:11])([CH3:10])[CH:8]1[CH:12]=[C:13]([Cl:15])[Cl:14])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.ClC1C=CC=[C:26]([C:30]([O:32]O)=[O:31])C=1.CSC>ClCCl>[C:30]([O:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C@H:7]1[C:9]([CH3:10])([CH3:11])[C@H:8]1[CH:12]=[C:13]([Cl:14])[Cl:15])(=[O:31])[CH3:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC(CC1C(C=C(Cl)Cl)C1(C)C)C(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)OC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)OC(C)=O
Temperature: 20 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
The contents of a 50-ml flask charged with 1-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]-3-oxo-2-butyl acetate prepared as in Embodiment VI above (11.9 mmol, 100% (1R,cis) both spatial configurations around C--C(O)CH3 present), chloroform (10 ml) and 3-chloroperbenzoic acid (26 mmol) were stirred magnetically for five hours at 20° C. Then, another quantity of 3-chloroperbenzoic acid (6 mmol) was added and stirring was continued for 16 hours. The reaction mixture obtained was continued for 16 hours. The reaction mixture obtained was mixed with dimethyl sulphide (2 ml), keeping the temperature at 20° C., stirring was continued for 15 minutes, dichloromethane (30 ml) was added, the suspended material was filtered off, the filtrate was washed with two 20-ml portions of a saturated aqueous solution of sodium hydrogen carbonate and two 20-ml portions of a 10%w aqueous solution of sodium chloride. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated (2 kPa) from the dried liquid to leave a residue (2.3 g) containing the desired (100% (1R,cis), yield 63%). The nuclear magnetic resonance spectrum of this product showed the following absorptions (using a solution of this product in deuterochloroform and relative to a tetramethylsilane standard):
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:11][C:7]1[C:6]2[C:2]([C:18]3[CH:17]=[CH:16][C:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[C:14]([O:13][CH3:12])[CH:19]=3)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccc2occ(Br)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2coc3ccnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
A mixture of 3-bromofuro[3,2-c]pyridin-4-amine (0.443 g, 2.1 mmol) in 1,2-dimethoxyethane (16 mL) and water (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.872 g, 2.5 mmol,), sodium carbonate (0.749 g, 7.1 mmol) and tetrakis triphenylphosphine palladium (0) (0.144 g, 0.12 mmol) at 80° C. for 18 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using heptane/ethyl acetate (4:1) followed by ethyl acetate as an eluents to give the title compound (0.734 g, 85%) as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.14 (d, 1H), 7.05 (dd, 1H), 6.94 (d, 1H), 5.55-5.62 (bs, 2H), 3.87 (s, 3H), 1.48 (s, 9H); RP-HPLC (Conditions f) Rt 12.13 min.; MS: MH+ 356.
Reaction SMILES: NC1N(C2C=CC=CC=2[O:13]C)N=CC=1C(N)=O.[NH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=[C:21]([CH3:30])[C:20]=1[C:31]#[N:32]>>[NH2:18][C:19]1[N:23]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:22]=[C:21]([CH3:30])[C:20]=1[C:31]([NH2:32])=[O:13]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Reactant: Cc1nn(C2CCOCC2)c(N)c1C#N
Product: Cc1nn(C2CCOCC2)c(N)c1C(N)=O

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CD3OD) δ 4.20 (m, 1H), 4.05 (m, 2H), 3.50 (m, 2H), 2.18 (s, 3H), 2.09 (m, 2H), 1.77 (m, 2H). MS: (M+H m/z 225.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:34][CH3:35])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:26])=[O:25])[CH3:22]>C(N(C(C)C)C(C)C)C>[CH2:34]([N:23]([CH2:21][CH3:22])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:25])=[O:26])[CH3:35]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCN(CC)S(=O)(=O)CCCCCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)S(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 93.9 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-diethyl-6-chlorohexanesulfonamide (511.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-diethyl-6-[4-[(4-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide (951.0 mg) as a pale brown oil (yield: 94.0%).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)=[O:21])C1C=CC=CC=1.C(O)C>[Pd].C(OCC)(=O)C>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([NH:22][C:20](=[O:21])[C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:9]=2[OH:8])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:24]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=1
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of 4-benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethyl-isophthalamide (141 mg, 0.28 mmol) and 5% Pd—C(14 mg) in the mixture of ethanol (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (106 mg, 91.2%) as a white solid.
Reaction SMILES: [CH:1]([N-:3][CH:4]=[O:5])=[O:2].[Na+].[Na+].[I-].Br[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(#N)C>[CH:1]([N:3]([CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[O:5])=[O:2]
Reactant: O=C[N-]C=O
Reactant: CCOC(=O)/C=C/CBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CN(C=O)C=O
Yield: 84.8 %

Procedure:
Prepared according to WO 2010/031816. In a 250 mL RBF, sodium diformylamide (Fluka; 2.66 g, 28.0 mmol) and NaI (3.49 g, 23.31 mmol) were treated with ACN (60 mL) and (E)-ethyl 4-bromobut-2-enoate (Aldrich; 4.28 mL, 23.31 mmol) and the flask was fitted with a reflux condenser and heated at reflux overnight (16 h). The mixture was concentrated in vacuo and the crude residue was treated with water and extracted with EtOAc (100 mL). The organic extract was washed with brine, then dried over MgSO4, filtered, and concentrated. The resulting light-brown solid was suspended in Et2O (ca. 10 mL), filtered, and washed with Et2O (5 mL), then dried by drawing air through the filtercake for 2 min to afford (E)-ethyl 4-(N-formylformamido)but-2-enoate (3.66 g, 19.76 mmol, 85% yield) as a brown amorphous solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (2H, br. s.), 6.74-6.84 (1H, m), 5.90 (1H, dt, J=15.8, 1.6 Hz), 4.40 (2H, d, J=4.5 Hz), 4.13-4.24 (2H, m), 1.20-1.33 (3H, m). m/z (ESI, +ve ion) 186.1 (M+H)+. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:11][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:10])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc([C@@H](C)Nc2nc(Cl)ncc2Cl)c1
Yield: 90.6 %

Procedure:
To a solution of (1R)-1-(3-methoxyphenyl)ethanamine (1.50 g, 9.92 mol) (R-isomer, >98% ee purity) and 2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.1 g, 30 mmol). The resultant mixture was stirred over two days at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, concentrated, and triturated with cold EtOAc to give the desired product as a light yellow gel (2.81 g, 95%). LCMS for C13H14Cl2N3O (M+H)+: m/z=298.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=3[S:11](=[O:23])(=[O:22])[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].O.C(O)C>O1CCOCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=3[S:11](=[O:23])(=[O:22])[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2N1CCOCC1

Procedure:
Stir 386 mg (1 mmole) of the ester of Example 19 in a solution of 131.8 mg (2 mmole) of 85% aqueous potassium hydroxide, 1.3 ml of water, 6.5 ml of ethanol and 0.65 ml of dioxane at room temperature under argon for 1 hour. Evaporate to dryness and dissolve the residue in 5 ml of water. Acidify with acetic acid, separate the precipitate by filtration, wash with water and dry. Recrystallize from methanol to obtain the title product (m.p. 200-295 dec).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[CH3:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([Cl:17])=[O:7])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(C)C)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C(C)C)c1C(=O)Cl
Reaction time: 15 h

Procedure:
A solution of 2-(1-methylethyl)-6-methylbenzoic acid (64 mg, 0.35 mmol) in dichloromethane (3 mL) containing DMF (2 drops) was treated with oxalyl chloride (0.16 mL, 1.8 mmol) and the mixture was stirred for 15 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step.
Reaction SMILES: OCC[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.N1[CH:21]=[CH:20]N=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:41]I>CCOCC.CCOCC.CC#N>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:9][CH:8]1[CH2:20][CH2:21][I:41])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: II
Reactant: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCCC1CCI
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-hydroxyethyl)-1-(t-butoxycarbonyl)-piperidine (4.5 g, 19.6 mmol, from EXAMPLE 113, Step A), imidazole (1.8 g, 27 mmol) and triphenylphosphine (7.1 g, 27 mmol) in 60 mL of 2:1 v/v ether/CH3CN at 0° C. was treated with 7.4 g (29 mmol) of iodine. The mixture was warmed to rt and stirred for 15 min. The mixture was diluted with 200 mL of ether and washed with sat'd Na2SO4 (2×200 mL), sat'd CaSO4 (100 mL) and sat'd NaCl. The organic phase was dried over Na2SO4 and concentrated. The material was filtered through a pad of silica to remove the triphenylphosphine oxide providing 6.1 g (92%) of the title compound: 1H NMR (300 MHz) δ 1.0-1.2 (m, 2H), 1.45 (s, 9H), 1.55 (m, 1H), 1.7-1.8 (m, 4H), 2.6-2.8 (m, 2H), 3.19-3.25 (t, 2H), 4.04.2 (m, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]#[N:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]>CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]([NH:2][OH:3])=[NH:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]
Reactant: NO
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45 %

Procedure:
Under Ar, a soln of hydroxylamine hydrochloride (119 mg, 1.72 mmol) and triethylamine (0.26 mL, 1.89 mmol) in 5 mL of DMSO was stirred at room temperature for 5 min, the product of Example 206, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-propionitrile (150 mg, 0.34 mmol) was added. The resulting mixture was heated to 80° for 16 h. Preparative hplc, followed by recrystallization from ethanol and hexane, gave the desired product 80 mg (45%). LC-MS: 469.2 (MH+, m/z), 1.52 (Rt, min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCSc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 4-bromobenzenethiol (10.1 g), and to the solution was added at room temperature potassium carbonate (9.6 g). To the mixture was added dropwise 1-iodohexane (9.5 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 1-bromo-4-(hexylthio)benzene (14.2 g). In THF (127 ml) was dissolved 1-bromo-4-(hexylthio)benzene (14.1 g), and to the solution was added dropwise at −78° C. 1.6M n-butyllithium/hexane (35.5 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (16.1 g) in THF (32 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (70.5 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(hexylthio)phenyl borate (6.6 g).