Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.O1CCC[CH2:31]1.C[Mg]I.C(OCC)C.Cl>O.C(OCC)(=O)C>[CH2:31]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2=O)OCO4)CC1
Agent: C[Mg]I
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1c2cc3c(cc2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCO3
Temperature: 5 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a reaction vessel, 75 g (0.19 mol) compound XI and 500 ml tetrahydrofuran were added while stirring under nitrogen, The mixture was cooled to 0-10° C., 400 ml 1.2N methylmagnesium iodide/ethyl ether solution was slowly added into the reaction vessel, the reaction was kept for 1 h, a minor amount of water was added until there was no bubble formed, concentrated hydrochloric acid was added to adjust the pH to acidic, the reaction was kept for 15 min, 500 ml ethyl acetate and 300 ml water were added, extracted, washed, the organic layer was collected, dried over sodium sulfate, filtered, the filtrate was concentrated to a minor amount, petroleum ether was added, solid was precipitated out, filtered, dried, and 47.6 g compound IX-1 was obtained, with yield of 63.8%. H NMR (DMSO-d6): δ 0.95-1.05 (m, 2H), 1.38 (s, 10H), 1.48 (q, 2H, J=7.0 Hz), 1.71 (d, 2H, J=12.2 Hz), 2.65 (br s, 2H), 3.70 (t, 2H, J=7.2 Hz), 3.90 (d, 2H, J=11.6 Hz), 4.95 (s, 1H), 5.34 (s, 1H), 6.17 (s, 2H), 7.15 (s, 1H), 7.53 (s, 1H); MS (ESI): m/z 423 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)c1
Yield: 12.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (106 mg, 0.17 mmol) was hydrolyzed with lithium hydroxide (36 mg, 0.861 mmol) in THF/water/methanol (12/6/2 ml) mixture to afford 10 mg (12.6% yield) of the pure product. 1H NMR (CD3OD, 300 MHz): δ 8.464-8.458 (d, 1H), 8.352-8.347 (d, 1H), 8.185 (s, 1H), 7.923 (s, 1H), 7.64 (s, 1H), 7.544-7.538 (m, 1H), 7.514-7.431 (m, 2H), 7.37-7.26 (m, 2H), 7.115-6.997 (m, 2H), 5.426 (s, 2H), 3.002 (s, 3H). MS: m/z=461.8 (M+1), HPLC: 96.947% in method A.
Reaction SMILES: C(O)(=O)C.O.[C:6]([CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[O:12][CH2:11][C:10]1=[O:22])#[N:7]>[Fe].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:10](=[O:22])[N:9]([CH2:8][C:6]#[N:7])[C:14]=2[CH:15]=1
Reactant: N#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CCN1C(=O)COc2ccc(N)cc21
Temperature: 80 °C
Yield: 74.4 %

Procedure:
A mixture of ethanol (15 ml), acetic acid (1 g), water (25 ml) and iron (3 g) is stirred at 80° C., and 4-cyanomethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.33 g) is added portionwise thereto. The whole is stirred at 80° C. until gas evolution ceases. The reaction mixture is mixed with active carbon (1 g) and ethanol (20 ml), refluxed for 15 minutes, and filtered. The filtrate is poured into chilled water. The deposited crystals are collected by filtration, and dried to obtain 6-amino-4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-one (1.51 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([C:29]3[N:34]=[CH:33][C:32]([C:35]4[CH:36]=[N:37][NH:38][CH:39]=4)=[CH:31][N:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:37]2[CH:36]=[C:35]([C:32]3[CH:31]=[N:30][C:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([C:21]5[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=5)[CH:24]=4)=[N:34][CH:33]=3)[CH:39]=[N:38]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Temperature: 120 °C
Yield: 170.1 %

Procedure:
4-Methanesulfonyloxy-cyclohexanecarboxylic acid ethyl ester (AOKChem Co., Ltd; 689 mg; 2.75 mmol; 1.04 eq.) in DMF (5 mL) was added in one portion to a suspension of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 104 mg; 0.34 mmol; 1.0 eq.) and cesium carbonate (2.35 g; 7.21 mmol; 2.7 eq.) in DMF (10 mL). The reaction mixture was heated in MW at 120° C. for 35 min. It was then poured into water and filtered. The resulting solid was triturated with ACN to give the title compound as a yellow solid (264 mg, 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.57-8.46 (m, 2H), 8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.77-7.66 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.32-3.99 (m, 3H), 3.89 (s, 3H), 2.48-2.34 (m, 1H), 2.23-1.48 (m, 8H), 1.27-1.14 (m, 3H). MS (ESI+): 457.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH2:6].[S:11](=[O:15])(=[O:14])([OH:13])N>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:6])[C:7]([CH3:10])=[CH:8][C:9]=1[S:11]([OH:15])(=[O:14])=[O:13]
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C)c(N)c1
Solvent: CC#N
Product: COc1cc(N)c(C)cc1S(=O)(=O)O
Reaction time: 2 h

Procedure:
23.1 g of 3-methoxy-6-methylaniline and 16.4 g of sulfamic acid were put into a 100 ml egg-plant type flask and the mixture was heated to temperature of from 150° to 160° C. and maintained thereat for 2 hours. Acetonitrile was added to the reaction mixture and the crystals thus deposited were collected. The crystals were dissolved in an aqueous solution of sodium hydroxide, the solution was filtered and acidified with hydrochloric acid, and the crystals thus deposited were collected by filtration.
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH:18][NH2:19].[OH-].[K+]>>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]([CH:5]1[CH2:6][CH2:7][S:1](=[O:3])(=[O:2])[CH2:4]1)[NH2:19]
Reactant: NNc1ccc2ccccc2c1
Reactant: O=S1(=O)CC=CC1
Agent: [K+]
Agent: [OH-]
Product: NN(c1ccc2ccccc2c1)C1CCS(=O)(=O)C1
Reaction time: 16 h

Procedure:
To a mixture of 0.5 mole of butadiene sulfone (commercially available from Aldrich, Milwaukee, Wis.) and 0.55 mole of 2-naphthylhydrazine is added 0.005 mole 40% aqueous potassium hydroxide solution. The mixture is kept for 16 hours at 60° C. N-(2-Naphthyl)-N-sulfolan-3-ylhydrazine is isolated and purified.
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[C:11]([F:27])[CH:10]=3)[C:6]=1[OH:28])=[O:4].[NH2:29][CH2:30][C:31]([O-:33])=[O:32].[Na+]>>[F:27][C:11]1[CH:10]=[C:9]2[C:14]([N:15]3[C:7](=[CH:8]2)[C:6]([OH:28])=[C:5]([C:3]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])[C:17](=[O:18])[N:16]3[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc3cc(F)ccc3n2n(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc3cc(F)ccc3n2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 7-fluoro-4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 428 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:38]([O:39][CH3:40])=[CH:37][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:24][C:25]2[C:38]([O:39][CH3:40])=[CH:37][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n1)CCN(CCO)CC2
Yield: 43 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. The product was isolated as a light yellow foam (40 mg, 43%). mp: 110° C., MS (ESI+): 573 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.66 (t, 2H), 3.28 (t, J=5 Hz, 4H), 2.89 (t, 2H), 2.74-2.69 (m, 8H), 1.80 (m, 4H).
Reaction SMILES: [C:1]1(=[N:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[N:19]=3)[C:8]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:1]1([NH:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:28])(=[O:29])[N:19]=3)[C:8]2=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 235A (0.030 g, 0.071 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.060 mL, 0.12 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 8 H) 3.70 (m, 1 H) 5.68 (d, J=4.41 Hz, 1 H) 7.05 (t, J=7.35 Hz, 1 H) 7.28 (t, J=8.27 Hz, 2 H) 7.54 (m, 2 H) 7.69 (dd, J=15.81, 8.09 Hz, 2 H) 8.06 (dd, J=8.09, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [Cl:1]C1C=C2C(=CC=1)C(CCCl)[O:7][CH2:6]C2.[OH2:15].[ClH:16].Cl.[CH:18]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3OC)[CH2:32][CH2:31]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]O1>>[ClH:1].[ClH:16].[Cl:16][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[CH:18]([CH2:28][CH2:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:7][CH3:6])=[CH:38][CH:37]=3)[CH2:34][CH2:35]1)[O:15][CH2:20][CH2:21]2
Reactant: ClCCC1OCCc2cc(Cl)ccc21
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: O
Agent: Cl
Product: COc1ccc(N2CCN(CCC3OCCc4cc(Cl)ccc43)CC2)cc1

Procedure:
Following the general procedure of EXAMPLE 1 and making non-critical variations but using 6-chloro-1-(2-chloroethyl)isochroman (LXIV, 0.2315 g, 0.972 mmol) and 1-(4-methoxyphenyl)piperazine dihydrochloride (XI, 0.3772 g, 1.00 mmol), the title compound is obtained, mp 203.5°-208°; MS (m/z) 386; IR (mineral oil) 1512, 2388, 1485, 1261, 1118 and 1105 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)=[O:8].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8].[F:23][C:24]([F:29])([F:28])[C:25]([O-:27])=[O:26]
Reactant: CN(C)CCOCC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOCC(=O)N[C@H]1CCNC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
(S)-3-[2-[2-(Dimethylamino)ethoxy]acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (175 mg) prepared in Step D was added with a 30% solution of trifluoroacetic acid in dichloromethane (5 ml), and the mixture was stirred at room temperature. The volatile components were removed to obtain the title compound as trifluoroacetate (246 mg).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=2[F:30])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO.C(OCC)(=O)C>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=1[F:30])=[O:11]
Reactant: CSc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncn23)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)cc3ccncn23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution of 7-(2-fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (246 mg, 0.56 mmol) in methanol (1 mL) was added a solution of hydrochloric acid in dioxane (1 mL, 4M, 4 mmol). The reaction was stirred at room temperature for 1 hour then diluted with ethyl acetate (5 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% DCM in methanol) to yield a light brown solid. The solid was triturated with acetonitrile (3 mL) to yield the title compound as a beige solid (100 mg, 45%). 1H NMR (DMSO-d6): 11.38 (1H, s), 8.64 (1H, t, J=1.05 Hz), 7.86 (1H, s), 7.41-7.39 (2H, m), 7.15 (1H, dd, J=12.09, 2.09 Hz), 6.82-6.79 (1H, m), 6.73 (1H, s), 6.06 (1H, t, J=8.82 Hz), 4.82 (1H, s), 4.53 (1H, s), 3.80 (1H, dd, J=9.68, 3.51 Hz), 3.67-3.57 (2H, m), 3.31-3.24 (2H, m). (SMe coincident with solvent). LCMS (Method A): RT=7.14 min, M+H+=407.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[OH:7])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)OCC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3g (1.19 g, 1.0 equiv) and EtOH (6 mL) was added at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (107.1 mg, 0.8 equiv) in H2O (2.4 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (11 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (100 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated under reduced pressure to afford crude 4g. The diastereomeric ratio of crude 4g was determined to be 95/5 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/1) to give a diastereomeric mixture of 4g (0.84 g, 82% yield) as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:18][N:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[O:21])[C:9]1=[O:30])(C)(C)C.C(O)(C(F)(F)F)=O>C(O)=O>[CH2:23]([O:22][N:19]([CH2:18][CH:10]1[C:9](=[O:30])[N:8]([CH2:7][C:6]([OH:31])=[O:5])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11]1)[CH:20]=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: O=CN(CC1Sc2ccccc2N(CC(=O)O)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
The {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid tert-butyl ester obtained in the previous step is treated with TFA (2.4 mmol) in 12 mL of formic acid. The reaction is stirred at room temperature for 3 hours. The solvent is removed and the mixture is purified by column chromatography (hexane/EtOAc) yielding {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid. Yield: 50%. MS: (ES+): 359.2 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([O:15][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17])[CH3:14]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[CH2:14])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(N)nc(SC)c1C#N
Temperature: 25 °C
Yield: 48.6 %

Procedure:
To a stirred solution of 300 mg (1.22 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml dioxane under argon at room temperature were added 0.41 ml (1.22 mmol) (1-ethoxyvinyl)tributylstannane and 86 mg (0.12 mmol) bis(triphenyl-phosphine)palladium(II) chloride. The reaction mixture was heated at reflux for 16 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (hexane then 1/1 ethyl acetate/hexane) followed by trituration in ether/hexane afforded 140 mg (48%) 2-amino-4-(1-ethoxy-vinyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 236 (M+, 17), 221 ([M—CH3]+, 61), 207 ([M—C2H5]+, 32), 192 ([M—C3H8]+, 100).
Reaction SMILES: O=C1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4](=[O:21])O1.Cl.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][O:29][NH2:30])=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][O:29][NH:30][C:4](=[O:21])[C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2[NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: N#Cc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNc2ccccc2C(=O)NOCc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of 4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-benzonitrile (Preparation 7D, 319 mg) and O-(4-chloro-benzyl)-hydroxylamine hydrochloride (preparation 9, 267 mg) in DMF (10 ml) was added N-ethyldiisopropylamine (0.4 ml). The reaction mixture was heated to 100° C. and stirred for 17 hours. The mixture was cooled to room temperature and water was added. The pale brown precipitated material was isolated by filtration and re-crystallised from ethanol and gave the title compound as a white solid material. 13C-NMR (DMSO-d6) δ 148.2, 145.9, 135.1, 132.8, 132.5, 132.3, 130.6, 128.2, 128.0, 127.7, 118.8, 114.8, 113.2, 111.4, 109.5, 75.9, 45.4.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1([C:18]2[CH:19]=[CH:20][C:21](=[O:31])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C1C=CN=CC=1)C.ClCCl>[O:31]=[C:21]1[N:22]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[C:18]([C:12]2([NH:11][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:19]=[CH:20]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1(c2ccc(=O)n(Cc3ccccc3)c2)CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1(c2ccc(=O)n(Cc3ccccc3)c2)CCCCC1
Yield: 99.7 %

Procedure:
Phenylacetyl chloride (1.6 g) was added to a well stirred suspension of 5-(1-aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone (2.9 g), poly-4-vinylpyridine (2.1 g) and a catalytic amount of 4-(N,N-dimethylamino)pyridine in 70 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate concentrated to give 4.1 g of oil. Column chromatography (silica gel, elution with ethyl acetate) afforded 2.1 g of foam. Recrystallization from ethyl acetate/hexanes gave 1.7 g of analytically pure product as needles, m.p. 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[C:16]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>ClCCl>[NH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:29]=[CH:30][C:14]([NH:13][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:15][C:16]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(OCCN)c(-c3c(Cl)cnn3C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-4-methoxybenzoic acid (92.8 mg, 545 μmol), tert-butyl 2-(4-amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (200 mg, 545 μmol), HATU (207 mg, 545 μmol) and triethylamine (76.0 μL, 545 μmol) in dichloromethane was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. To the crude product was added 2M HCl (5 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated and the title compound was obtained as a yellow oil. LCMS m/z (%)=419 (M+H, 35Cl, 100), 421 (M+H, 37Cl, 40).