Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:42][C:43]([C@@H:45]([NH:50][C:51](=[O:54])[O:52][CH3:53])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]([O:38][CH2:39]SC)[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:55](=[O:59])([OH:58])([OH:57])[OH:56].IN1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+:72].[Na+:73]>O1CCCC1.CO>[CH3:53][O:52][C:51](=[O:54])[NH:50][C@@H:45]([C:46]([CH3:47])([CH3:48])[CH3:49])[C:43](=[O:44])[NH:42][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([O:38][CH2:39][O:57][P:55]([OH:59])([OH:58])=[O:56])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:35])([CH3:34])[CH3:36])[NH:28][C:29](=[O:30])[O:31][CH3:32].[Na:72][Na:73]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCSC)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Reactant: O=P(O)(O)O
Reactant: [Na+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCOP(=O)(O)O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Product: [Na][Na]
Yield: 56 %

Procedure:
A solution of Example 204A (2.46 mg, 3.2 mmol) in tetrahydrofuran (16.0 mL) was treated with 4 Å molecular sieves (8.0 g), a solution of phosphoric acid (32.0 mL, 0.5 M in DMF), and N-iodosuccinimide (1.45 g, 6.4 mmol) at 25° C. for 45 minutes. The mixture was poured into cold 10% sodium carbonate, diluted with methanol, filtered and through celite. The filtrate was decolorized with saturated sodium thiosulfate and concentrated. The resulting concentrate was dissolved in methanol, filtered and concentrated. Methanol and water were added to the resulting concentrate and the pH was adjusted to 9 by addition of 10% Na2CO3, and the mixture was purified by reverse phase HPLC using a C18 column, eluting with a gradient starting with water and ending with methanol, to give the title compound as a disodium salt (1.53 g, 56% yield). 1H NMR (300 MHz, MeOH-d4), δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H), 1.67-1.76 (m, 1H), 2.00-2.10 (m, 1 H), 2.68-2.99 (m, 4 H), 3.54 (s, 3 H), 3.65 (s, 3 H), 3.70-3.74 (m, 1 H), 3.93 (s, 1 H), 3.94 (s, 1 H), 4.22-4.32 (m, 1 H), 4.34-4.38 (m, 1 H), 5.02 (dd, J=8.8, 5.5 Hz, 1 H), 5.15 (dd, J=8.8, 5.2 Hz, 1 H), 7.05-7.33 (m, 8 H), 7.77-7.89 (m, 4 H), 8.56 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[CH2:49]([O:51][C:52](=[O:56])[C@@H:53]([OH:55])[CH3:54])[CH3:50].[H-].[Na+]>C1COCC1>[CH2:49]([O:51][C:52](=[O:56])[C@@H:53]([O:55][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)[CH3:54])[CH3:50]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CCOC(=O)[C@H](C)O
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step (0.77 g), THF (15 mL), 2-hydroxy-(2S)-propanoic acid ethyl ester (0.40 mL) and 60% sodium hydride (0.14 g) to give the subtitle compound as a clear, colourless oil. Yield: 1 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].[CH3:14][C:15]1[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.C1(C=O)CCCCC1>O.CC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: O=CC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCn1c(C2CCCCC2)nc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred and refluxing (water-separator) mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol and 0.1 parts of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise a solution of 34 parts of cyclohexanecarboxaldehyde in 45 parts of methylbenzene. Upon completion, stirring is continued for 1 hour at reflux temperature with water-separator. The methylbenzene is removed by evaporation in vacuo and the residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 16.5 parts (38%) of 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol; mp. 95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][N+:21]([O-])=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[C:22]([C:26]#[N:27])[N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CN(C)C(=O)Cl
Reactant: CC(c1cc[n+]([O-])cn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(c1cc(C#N)ncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of part (i) (0.80 g) and N,N-dimethylcarbamoyl chloride (0.50 g) in dichloromethane (10 ml) was stirred at room temperature for 2 hours. Trimethylsilyl cyanide (0.50 g) was added and stirring was continued for a further 6 days. The solution was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ methanol (100:1) gave a product which was rechromatographed on silica gel. Elution was commenced with ether and the polarity of the eluant was gradually increased by the addition of up to 6% (by volume) of methanol. Combination and evaporation of the initial product-containing fractions gave 2-(2,4-difluorophenyl)-3-(6-cyanopyrimidin-4-yl)-1-(1H-1,2,4-triazol-l-yl)butan-2-ol, m.p. 148°-149°.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[C:18](N1C=CN=C1)([N:20]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([NH:20][CH3:18])=[O:17]
Reactant: COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cnn(-c2ccc(OC)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To a solution of 1.2 g of 5-chloro-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid in 150 ml DMF was added 1.1 g of carbonyldiimidazole and the mixture was allowed to stir at room temperature for 20 minutes. One gram of triethylamine and 0.6 g of methylamine hydrochloride were next added to the reaction mixture and the solution was stirred at room temperature for 20 hours. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was separated and washed with water, dried, and concentrated under vacuum to dryness. The residue was recrystallized from toluene/hexane to afford 650 mg of 5-chloro-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-4-carboxamide. Yield 71%. mp=144°-146° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl[CH2:13][C:14](=[O:16])[CH3:15]>>[O:16]=[C:14]([CH3:15])[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(=O)CCl
Reactant: O=C(O)Cc1ccccc1S
Product: CC(=O)CSc1ccccc1CC(=O)O

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 2-mercaptophenylacetic acid and chloroacetone.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH:25]([CH3:32])[CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([Cl:33])=[CH:20][N:19]=1>>[Cl:33][C:21]1[C:22]([NH:24][CH:25]([CH3:32])[CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CC(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NC(C)CNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-propyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-propyl]-methanesulfonamide in an analogous manner to Example 302. Product isolated as a white foam (117 mg, 71%). LCMS (m/e) 483 (M+1); 1H-NMR (CDCl3, 400 MHz) δ7.94 (s, 1H), 7.32 (d, 1H, J=8.0 Hz), 7.24 (s, 1H), 7.04 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 5.35-5.27 (m, 1H), 5.22 (d, 1H, J=7.0 Hz), 4.41-4.31 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.46-3.35 (m, 1H), 3.38 (s, 3H), 3.29-3.20 (m, 1H), 2.96-2.86 (m, 4H), 2.91 (s, 3H), 2.80-2.68 (m, 6H), 1.36 (d, 3H, J=6.7 Hz).
Reaction SMILES: C([O:4][CH:5]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]2[CH:24]=[N:25][N:26]=[C:6]12)(=O)C.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:4][CH:5]1[C:11](=[O:12])[N:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]2[CH:24]=[N:25][N:26]=[C:6]12
Reactant: CC(=O)OC1C(=O)N(c2ccccc2)c2cc(Cl)ccc2-n2cnnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1C(O)c2nncn2-c2ccc(Cl)cc2N1c1ccccc1

Procedure:
3.5 g of 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.8 ml of 4N aqueous sodium hydroxide in 160 ml of ethanol are stirred overnight at 25°. The reaction is neutralized with 0.5 g of acetic acid and the solvent is evaporated. The residue is partitioned between chloroform and water, the organic phase is dried and the solvent evaporated to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13]C(O)=[C:11](C)[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:5]([O:4][C:1]1[CH:11]=[CH:10][C:9]([OH:8])=[C:14]([CH3:13])[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)Oc1ccc(O)c(C)c1
Reaction time: 8 h
Yield: 3.1 %

Procedure:
Acetic anhydride (4.73 gm, 4.37 mL, 46.3 mMol) was added dropwise to a mixture of 4-hydroxy-2-methylphenol (5 gm, 46.3 mMol) and cesium carbonate (15.1 gm, 46.3 mMol) in acetonitrile (50 mL). After stirring overnight, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5:1 pentane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.24 gm (3%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:18][N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]1=2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 1 h

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (231 mg, 0.986 mmol), cesium carbonate (650 mg, 2 mmol), iodomethane (123 uL, 2 mmol) and DMF (6 mL). Stirred at room temp. for 1 hour. Evaporated off solvent, added water and extracted into methylene chloride. Dried organic layer over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow solid, 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. mp 115° C.; LCMS: m/z=249.07 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H, J=2.3 Hz), 8.19 (dd, 1H, J=8.7, 2.3 Hz), 7.34 (d, 1H, J=8.6 Hz), 3.37 (s, 3H), 2.34 (m, 2H), 2.14 (m, 2H), 1.43 (s, 6H).
Reaction SMILES: C(OC(=O)NC[C@H]1CC[C@H](C2N3C(C(N)=NC=N3)=C([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)N=2)CC1)C1C=CC=CC=1.[CH3:42][O:43][C:44]([C@H:46]1[CH2:51][CH2:50][C@H:49]([C:52]2[N:60]3[C:55]([C:56]([NH2:61])=[N:57][CH:58]=[N:59]3)=[C:54](I)[N:53]=2)[CH2:48][CH2:47]1)=[O:45]>>[CH3:42][O:43][C:44]([C@H:46]1[CH2:47][CH2:48][C@H:49]([C:52]2[N:60]3[C:55]([C:56]([NH2:61])=[N:57][CH:58]=[N:59]3)=[C:54]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:30][CH:29]=3)[N:53]=2)[CH2:50][CH2:51]1)=[O:45]
Reactant: Nc1ncnn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)ncnn32)CC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
Prepared according to the procedure analogous to that described above for trans-{4-[4-amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl}-carbamic acid benzyl ester, except using trans-4-(4-amino-5-iodo-imidazo[5,1-f][1,2,4]triazin-7-yl)-cyclohexanecarboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:12])[CH2:11][CH2:10][CH2:9]1.[CH:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C.CCCCCCC>[C:16]([O:15][C:13]([N:12]([CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC=O
Reactant: C=CC(=O)OCC
Reactant: NC1CCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)C1CCC1

Procedure:
The title compound was prepared from ethyl acrylate (1.09 ml, 10 mmol) and cyclobutylamine (0.85 ml, 10 mmol) according to Example 2a. Yield: 1.71 9 (63%). ESI-MS: 272.2 (M+H)+, 216.2 (M+H—C4H8)+, 172.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.44.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([OH:17])=O)=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:17])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: NCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 71 %

Procedure:
4-(4-Bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in a mixture of anhydrous THF and anhydrous DMF and treated with 3-amino-1-propanol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-(4-bromo-2-fluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (71%) as a cream solid; m.p. (EtOAc/Hexane) 167-170° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.10 (br s, 1H), 8.40 (t, J=5.3 Hz, 1H), 8.24 (s, 1H), 7.69-7.64 (m, 1H), 7.48-7.40 (m, 2H), 5.56 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.37 (s, 3H), 3.27 (dd, J=12.7, 6.9 Hz, 2H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 398 (85%), 396 (100%). Anal. Calcd for C16H17BrFN3O3: C, 48.3; H, 4.3; N, 10.6. Found C, 48.2; H, 4.2; N, 10.5.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14][CH:15]=C[C:11]=2[N:10]=N1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43](O)=[O:44])=[C:35]2[CH:34]=[N:33]1.NC1C=NC=CN=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.O>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2[N:37]=[CH:38][N:39]=[C:40]([O:41][CH:42]([CH2:46][O:47][CH:48]([CH3:49])[CH3:50])[C:43]([NH:8][C:12]3[CH:11]=[N:10][CH:15]=[CH:14][N:13]=3)=[O:44])[C:35]=2[CH:34]=[N:33]1
Reactant: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)OCC(Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (333 mg, 0.88 mmol) was added to (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoic acid (Intermediate D2) (300 mg, 0.80 mmol), aminopyrazine (CAS no. 5049-61-6) (84 mg, 0.88 mmol) and N-ethyldiisopropylamine (0.153 mL, 0.88 mmol) in DCM (15 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (10 mL) and water (10 mL) and the organic phase separated using a phase separation cartridge and evaporated. The residue was purified using reverse phase chromatography, eluting with 25-75% acetonitrile in water to give 2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-isopropoxy-N-pyrazin-2-yl-propanamide (142 mg, 39%). 1H NMR (400 MHz, CDCl3) 1.18-1.22 (6H, m), 3.70-3.78 (1H, m), 4.10 (2H, d), 6.08 (1H, t), 7.40-7.50 (2H, m), 7.51-7.55 (1H, m), 7.62-7.64 (1H, m), 8.24 (1H, s), 8.35 (1H, s), 8.60 (1H, s), 8.80 (1H, s), 9.58 (1H, s); (M+H)+=454; HPLC tR=2.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([F:19])[CH:13]=[C:12](F)[C:11]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([F:19])[CH:13]=[C:12]([O:23][CH3:22])[C:11]=1[F:21]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 456.4 %

Procedure:
To a solution of 2-fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-iodobenzeneamine (2.55 g, 6.16 mmol) in THF (40 mL), was slowly added NaOMe solution (25% in MeOH, 1.4 mL, 0.62 mmol) at −78° C. The mixture becomes dark in color immediately. After the addition was complete, the reaction mixture was warmed to rt and stirred overnight. It was then diluted with ethyl acetate and washed with water, brine and then dried. After removal of volatiles, the crude product was purified by silica gel flash column using 2-10% ethyl acetate/hexanes as eluent to produce the desired product as yellow powder (1.2 g, 48%). Unreacted starting material 2-fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-iodobenzeneamine (1 g) was also recovered.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH:20]([CH3:22])[CH3:21])[C:8](=[O:23])[NH:7][C:6]1=[O:24])[C:2]#[C:3][CH3:4].N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>CO.[Pd]>[CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:9]([CH:20]([CH3:21])[CH3:22])[C:8](=[O:23])[NH:7][C:6]1=[O:24])/[CH:2]=[CH:3]\[CH3:4]
Reactant: CC#CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Solvent: c1ccncc1
Product: C/C=C\Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 33 mg (0.1 mmol) of the compound obtained from Example 11 in 1 ml of methanol were added 3 ml of pyridine, a drop of quinoline, and 4 mg of palladium on barium sulfate. The reaction mixture was then stirred for about 2 hours at room temperature under an atmosphere of hydrogen, filtered through Cellite pad, and evaporated under reduced pressure to give a light brown oil, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:3) as an eluent to afford 25 mg (yield 76%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][O:4][C:5]3[CH:6]=[C:7]([C:11]4[C:15]5[S:16][CH:17]=[CH:18][C:14]=5[O:13][N:12]=4)[CH:8]=[CH:9][CH:10]=3)[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(CCOc3cccc(-c4noc5ccsc45)c3)CC2)cc1
Yield: 66 %

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, and N-phenylpiperazine essentially as described in example 27 except that the freebase is dried to give the title compound (330 mg, 66%). Mp=91–93° C. Microanalysis (C, H, N) is consistent with the final compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C@H:18]2[CH2:20][C@H:19]2[CH2:21][CH2:22][OH:23])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:10]([O:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([C@H:18]3[CH2:20][C@H:19]3[CH2:21][CH2:22][OH:23])[CH2:14][CH2:13]2)=[N:7][CH:6]=1)[CH3:11]
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CCOCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In a 250 ml RBF 2-chloro-5-(ethoxymethyl)pyrimidine (280 mg, 1.622 mmol) and 2-[(1S,2R)-2-(piperidin-4-yl)cyclopropyl]ethanol (334 mg, 1.622 mmol) were dissolved in DMF (1622 μl). Cesium carbonate (1586 mg, 4.87 mmol) was added and the mixture stirred at 70° C. overnight. The mixture was diluted with 4:1 water:brine (200 ml), extracted with EtOAc (3×100 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuo. The mixture was purified on a 100 g Biotage HP-SiO2 cartridge using a gradient eluant of 0-100% EtOAc:hexanes to afford the title compound. LC/MS (m/z): 306 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=O.O.[NH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16].N1[C:21]2C=CC=C[C:20]=2N=N1.C(C=O)=O.[BH4-].[Na+]>O.C(O)C>[CH3:4][C:2]12[CH:1]3[N:7]4[CH2:20][CH2:21][N:16]3[CH2:15][CH2:14][N:13]1[CH2:12][CH2:11][N:10]2[CH2:9][CH2:8]4
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(=O)C=O
Reactant: NCCNCCNCCN
Agent: O=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC12C3N4CCN3CCN1CCN2CC4
Temperature: 2 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A 40% strength solution of 61.56 g of pyruvaldehyde in water (342 mmol) in 100 ml of water is added by slow dropwise addition INto a solution of 60.66 g (342 mmol) of triethylenetetraamine hydrate (containing 17% water) in 300 ml of distilled water cooled to 2° C. On completion of addition, the reaction mixture is adjusted to ambient temperature and 81.40 g (684 mmol) of benzotriazole are added in a single portion. 300 ml of ethanol are then added to the reaction medium, then a solution of 49.59 g of glyoxal (40% in water) (342 mmol) in 100 ml of ethanol is added by slow dropwise addition. After 2 h of stirring at ambient temperature, the solution is cooled to 0° C. and 25.87 g (684 mmol) of NaBH4 are added in small portions. After returning to ambient temperature, the reaction medium is stirred for 2 h, the ethanol is evaporated and 70 g of KOH pellets are added to the residue. The solution is then extracted with two 1 l portions of chloroform. After drying over MgSO4 and evaporation of the solvents, (IIb) is isolated in the form of an orange oil (32.3 g; yield=45%).