Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10]C)=[C:6]([CH:9]=1)[CH:7]=[O:8].C(C1C(O)=C(C=CC=1)C=O)(C)(C)C.BrBr>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1c(C=O)cc(Br)cc1C(C)(C)C
Agent: BrBr
Agent: CC(C)(C)c1cccc(C=O)c1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Reaction time: 1 h

Procedure:
5-bromo-3-tert-butyl-2-methoxybenzaldehyde (28)—To a solution of 3-tert-butyl-2-hydroxybenzaldehyde (CASRN 24623-65-2, 5.00 g) DCM (20 mL) at 0° C. was added dropwise a solution of Br2 (1.45 mL) in DCM (15 mL) over a period of 30 min. After the addition was complete the reaction was stirred for 1 h before the organic volatiles were removed under reduced pressure to afford 7.23 g of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde (27) as a light yellowish solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([CH3:23])[CH:19]=[C:18]([OH:24])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:25](=[O:27])[NH2:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([CH3:23])[CH:19]=[C:18]([O:24][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:25](=[O:27])[NH2:26])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
60% Sodium hydride in mineral oil (30.4 mg, 0.76 mM) was added to a solution of 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole (202 mg, 0.61 mM) in 21 mL DMF and 4.6 ml THF. After 10 minutes, methyl bromoacetate (77 μl, 0.482 mM) was added and the resultant mixture stirred at room temperature for 1.25 hours. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 184 mg (75%) of {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ 7.55 (d, 1H, J=8 Hz), 7.5 (bs, 1H), 7.4-7.15 (m, 9H), 6.45 (s, 1H), 5.7 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), 2.4 (s, 3H). MS (FD) m/e 386, 403.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH2:12][C:13]([CH3:18])([CH2:16][OH:17])[CH2:14][OH:15]>>[OH:15][CH2:14][C:13]([NH:12][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9])([CH2:16][OH:17])[CH3:18]
Reactant: CC(N)(CO)CO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Yield: 26.1 %

Procedure:
Prepared by general procedure III from 5-bromo-pyridine-3-sulfonyl chloride (Example B.2 step 2) (500 mg, 2 mmol) and 2-amino-2-methyl-1,3-propanediol (1.03 g, 10 mmol) to give the title compound as a light brown oil (170 mg, 26%). MS (ISP) 325.1 [(M+H)+], 327.2 [(M+2+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:5]=1)([O-:3])=[O:2].C1C=C2C(N(O)N=NC2=CC=1)=O.Cl.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][S:40][CH3:41])[NH2:37].CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][S:40][CH3:41])[NH:37][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: Cc1ccccc1-c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
The product of Example 308A (604 mg, 2.35 mmol) and HOOBT (574 mg, 3.52 mmol) were dissolved in DMF (10 mL) and methionine methyl ester HCl (679 mg, 3.52 mmol) and EDCI (676 mg, 3.52 mmol) were added followed by Et3N (476 mg, 0.65 mL, 4.7 mmol). The reaction was stirred for 12 hours and then was taken up in ethyl acetate and washed successively with brine (3×) and water (3×). The ethyl acetate layer was dried over Na2SO4, filtered and evaporated. Purification by chromatography on silica gel (5% methanol-ethyl acetate) gave the desired compound (940 mg, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[N:30]1([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:42][CH:41]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCOCC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.28 g, 0.068 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.013 g, 0.068 mmol) were combined in i-PrOH (1 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 22 mg (62%) of 8-indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (br s, 1H), 8.55 (s, 1H), 7.44 (d, 2H, J=7.6 Hz), 7.05-7.30 (m, 5H), 4.40 (q, 2H, J=7.1 Hz), 3.71 (br s, 4H), 3.43 (s, 2H), 3.09 (t, 2H, J=7.5 Hz), 3.02 (t, 2H, J=7.2 Hz), 2.42 (br s, 4H), 2.21-2.31 (m, 2H), 1.40 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH2:22]4)[C:14]=3[S:13][CH:12]=2)=[O:10])[CH:7]=1.[CH3:25][C:26]1[N:27]=[CH:28][N:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[C:40]([F:43])([F:42])[F:41])[CH:30]=1>>[CH:21]1([NH:20][C:19]2[C:14]3[S:13][CH:12]=[C:11]([C:9]([NH:8][C:6]4[CH:7]=[C:2]([NH:1][C:35](=[O:36])[C:34]5[CH:38]=[CH:39][C:31]([N:29]6[CH:30]=[C:26]([CH3:25])[N:27]=[CH:28]6)=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:33]=5)[CH:3]=[CH:4][C:5]=4[CH3:24])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:22][CH2:23]1
Reactant: Cc1cn(-c2ccc(C(=O)O)cc2C(F)(F)F)cn1
Reactant: Cc1ccc(N)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Product: Cc1cn(-c2ccc(C(=O)Nc3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cc2C(F)(F)F)cn1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using N-(5-amino-2-methylphenyl)-4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamide and 4-(4-methyl-1H-imidazole-1-yl)-3-(trifluoromethyl)benzoic acid to obtain the title compound.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[C:17]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:23]1)C[C:18]2=O>COC(OC)(C)C>[C:1]([CH2:3][C@H:4]1[O:16][C:17]([CH3:23])([CH3:18])[O:15][C@@H:6]([CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: COC(C)(C)OC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, 15 g (61 mol), is dissolved in 150 mL of 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuo provides 11.8 g of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate as an off-white solid, mp 64.7°-68° C. with acceptable IR, NMR, C-NMR and analysis.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[C:29]2[N:28]=[CH:27][N:26]([CH3:30])[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[C:29]2[N:28]=[CH:27][N:26]([CH3:30])[C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: Cn1cnc2c(O)cccc21
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc2c1ncn2C
Yield: 38 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 4-hydroxy-1-methyl-1H-benzimidazole, the desired product is obtained in the form of a white solid with a yield of 38%. The product obtained is used directly in the deacetylation step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.C(Cl)(=O)C.Cl[C:45]([O:47][CH3:48])=[O:46]>>[CH:27]([O:26][C:24]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[C:4]1[S:3][C:2]([NH:1][C:45]([O:47][CH3:48])=[O:46])=[N:6][CH:5]=1)[CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]2=[O:23])=[O:25])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Solvent: CC(=O)Cl
Product: COC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1

Procedure:
3-(2-Amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.13 g) is treated in accordance with the working method described in Example 1 (B), the acetyl chloride being replaced by methyl chloroformate (0.19 cc). The crude product obtained is chromatographed on a column (height: 30 cm, diameter: 3 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a 40:60 (by volume) mixture of cyclohexane and ethyl acetate; 50 cc fractions are collected and are analysed by chromatography on a thin layer of silica gel (eluant: a 40:60 (by volume) mixture of cyclohexane and ethyl acetate). The fractions containing the pure expected product (Rf=0.3) are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.73 g) is obtained in the form of a yellow froth.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][OH:33])[CH:30]=2)[CH:25]=[CH:24]1.[OH-].[Na+]>C(Cl)Cl>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=[O:33])[CH:30]=2)[CH:25]=[CH:24]1
Reactant: OCc1ccc2cc[nH]c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Dess-Martin periodinane (1.53 g, 2.6 mmol) was dissolved into methylene chloride (15 mL). Indol-6-yl-methanol (500 mg, 3.4 mmol) in methylene chloride (12 mL) was added and the mixture was stirred for 1 hr. Sodium hydroxide (5 mL of 1 N solution) was added and the reaction was stirred for 15 min. The organic layer was separated and washed with H2O (5 mL), brine (5 mL), dried over MgSO4 and concentrated to afford the title compound as a brown solid (275 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 11.7 (s, 1H), 9.98 (s, 1H), 7.97 (s, 1H), 7.70-7.65 (m, 2H), 7.52 (dd, J=8.2, 1.4 Hz, 1H), 6.57-6.5 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([Cl:43])=[CH:23][N:22]=1>>[Cl:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.030 g, 37%). MP: 165-167° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (d, 1H, J=8.8 Hz), 8.10 (s, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 6.62 (s, 1H), 6.58-6.55 (m, 1H), 6.54-6.50 (s, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.24-3.18 (m, 4H), 2.90-2.77 (m, 10H), 2.64-2.57 (m, 4H), 2.37 (s, 3H), 1.68 (t, 3H, J=18.9 Hz). MS: 602 (MH)+.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([NH:38][CH3:39])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:18][CH:19]=1)[C:36]([NH:38][CH3:39])=[O:37])#[N:34]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: CNC(=O)CC#N
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CNC(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Yield: 95.7 %

Procedure:
To a 50 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.0005 mole) and 2-cyano-N-methylacetamide (0.22 g, 0.0022 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (1.0 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 2 hr. After completion of the reaction, ethanol was distilled out under vacuum and water was added to the residue. The aq. layer was extracted with ethyl acetate. Combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.255 g of 2-cyano-N-methyl-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide which was converted to the title compound as described in Example 1, Step 2 above.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8](=[O:12])[CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C[Si]([I:25])(C)C.II.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[I:25][CH:9]1[C:8](=[O:12])[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: O=C1CCCc2cccnc2N1
Reactant: C[Si](C)(C)I
Agent: CN(C)CCN(C)C
Agent: II
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: O=C1Nc2ncccc2CCC1I
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg of 5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one in 3 mL of dichloromethane at 0° C. was added 0.84 mL of N,N,N',N'-tetramethylethylenediamine (TMEDA) and 0.78 mL of trimethylsilyl iodide. After 30 min, 720 mg of solid iodine was added in one portion. The reaction mixture was stirred at 0° C. an additional 40 min before dichloromethane and excess aqueous sodium sulfite was added to reduce the excess iodine. The mixture was extracted with dichloromethane and the extracts were evaporated to yield 550 mg of the crude product. Flash chromatographic separation on silica gel with ethyl acetate gave 333 mg of purified product characterized by its NMR and mass spectra.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: COC1CCCC(N)C1
Solvent: c1ccncc1
Product: COC1CCCC(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of 3-methoxycyclohexanamine (0.200 g, 1.5 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.144 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 16 hrs and then concentrated. The mixture was diluted with ethyl acetate and washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.140 g, 44%). The material was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:18])[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C:5]1([CH3:18])[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: CC1(CN=[N+]=[N-])CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(CN)CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 88800.1 %

Procedure:
A mixture of 5-(azidomethyl)-3-(5-chloropyridin-2-yl)-5-methyl-1,3-oxazolidin-2-one (570 mg, INTERMEDIATE 18) and triphenylphosphine (1.12 g) was heated to 65° C. for 4 h in 80 ml of tetrahydrofuran and 10 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (4 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (4 column volumes), to provide the title compound (457 g, 89%). Mass spectrum (ESI) 242.1 (M+1).
Reaction SMILES: CC([O:4]C(/N=N/C(OC(C)C)=O)=O)C.OCCC1N=CSC=1C.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:37]1([P:30](=[O:4])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cc1scnc1CCO
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
DIAD (3.16 ml, 16.1 mM) was added to a stirred solution of methyl 3-nitro-5-hydroxy benzoate (2.11 g, 10.7 mM), 4-(2-hydroxy ethyl)-5-methylthiazole (1.55 ml, 12.8 mM), and triphenylphosphine (4.21 g, 16.1 mM) in THF (50 ml) under an argon atmosphere at room temperature. After 1 hr reaction mixture concentrated in vacuo, residue triturated with diethyl ether to give a colourless solid (triphenylphosphine oxide). Diethyl ether conc. to give a dark brown gum, purification on silica gel (50% to 75% EtOAc/iso-hexane) gave the product contaminated with reduced DIAD and triphenylphosphine oxide (6.8 g). The crude product was dissolved/suspended in MeOH (80 ml), 2M NaOH (20 ml, 40 mM) added, heated at 65° C. for 4 hrs then cooled and concentrated. The residue was diluted with water (140 ml)/2M NaOH (40 ml), the precipitated triphenylphosphine oxide filtered, then acidified with c. HCl to pH 1-2. The precipitate was filtered, washed with water, dried under high-vacuum to give 3-{2-(4-methyl thiazol-5-yl)ethoxy}-5-nitro benzoic acid as a colourless solid (3.12 g, 79% over 2 steps); 1H NMR δ (d6-DMSO): 2.39 (s, 3H), 3.23 (t, 2H), 4.35 (t, 2H), 7.78 (s, 1H), 7.90 (m, 1H), 8.22 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCBr
Reactant: Oc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(F)c1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
3-Fluorophenol (8.9 g, 79.5 mmol) and 3-bromopropionic acid (12.24 g, 80.0 mmol) were placed in a flask. A solution of NaOH (6.7 g, 167 mmol) in 20 mL water was added slowly to the flask. The reaction mixture was heated to reflux for two hours and then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, and solvent was evaporated under reduced pressure to give 4.57 g (25 mmol, 31.4%) of 3-(3-fluoro-phenoxy)-propionic acid. MS: 185 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:39][CH:38]=1)[NH2:35].[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]1[CH:64]=[C:63]([C:65](O)=[O:66])[O:62][N:61]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:41][CH:42]=1)[NH:35][C:65]([C:63]1[O:62][N:61]=[C:60]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[F:53])[CH:64]=1)=[O:66]
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
EDCI (92 mg, 480 μmol) and HOBT (65 mg, 480 μmol) were added to a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (108 mg, 240 μmol) and 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (50 mg, 240 μmol) in DMF (20 mL). DIPEA (62 mg, 480 μmol) was added and the mixture was stirred for 5 hours at room temperature. The mixture was washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc=1:1) to yield the title compound as a white solid (58 mg). LC-MS: 640.2 [M+H]+. 1H-NMR: (CDCl3) 2.07 (s, 3H), 3.43 (br, 2H), 4.4-4.2 (m, 2H), 4.3 (br, 1H), 4.94-4.86 (m, 2H), 7.24-6.85 (m, 5H), 7.97-7.27 (m, 8H).