Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Br:23])[CH:21]=[CH2:22]>C1(C)C(C)=CC=CC=1>[Br-:23].[CH2:22]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:21]=[CH2:20]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCBr
Solvent: Cc1ccccc1C
Product: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 30 °C

Procedure:
86.7 parts of triphenylphosphine was dissolved in 200 parts of xylene and 40.0 parts of allyl bromide was added thereto. The mixture was gradually heated and allowed to react at 134° C. for 3 hr. After the mixture was cooled to 30° C., the resulting colorless crystals were collected by filtration and washed with toluene to obtain 122.7 parts of allyltriphenylphosphonium bromide (compound No. 16).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18]([C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1)([OH:23])[CH2:19]2>CCO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[Cl:7])[N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18]([C:24]1[N:25]=[C:26]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:27]=[CH:28][N:29]=1)([OH:23])[CH2:19]2
Reactant: C1CNCCN1
Reactant: OC1(c2nccc(Cl)n2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Solvent: CCO
Product: OC1(c2nccc(N3CCNCC3)n2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
Add piperazine (20 mg, 0.23 mmol) to a solution of the product of Step 2 (25 mg, 0.05 mmol) in EtOH (4 ml) at RT. Stir the reaction mixture at 80° C. overnight. Extract and purify to produce the title compound (20 mg). 1H NMR (CDCl3) δ8.24 (d, 1H), 7.93 (d, 2H), 7.26 (d, 2H), 7.22 (t, 2H), 7.10 (t, 2H), 6.33 (d, 1H), 5.64 (s, 1H), 3.67 (s, br, 4H), 3.15 (s, br, 2H), 2.95 (m, 4H), 2.59 (dd, 2H), 2.34 (m, 2H), 2.17 (m, 2H), 1.57 (d, br, 2H).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[N:52][C:51]([N:54]3[CH2:59][CH2:58][CH:57]([NH:60][CH3:61])[CH2:56][CH2:55]3)=[C:50]([CH3:62])[C:49]=2[CH3:63])=[CH:44][CH:43]=1.[CH3:64][O:65][C:66]1[CH:84]=[CH:83][C:69]([CH2:70][N:71]2[CH:75]=[C:74]([C:76](O)=[O:77])[C:73]([C:79]([F:82])([F:81])[F:80])=[N:72]2)=[CH:68][CH:67]=1>CN(C=O)C>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[N:52][C:51]([N:54]3[CH2:59][CH2:58][CH:57]([N:60]([CH3:61])[C:76]([C:74]4[C:73]([C:79]([F:80])([F:81])[F:82])=[N:72][N:71]([CH2:70][C:69]5[CH:68]=[CH:67][C:66]([O:65][CH3:64])=[CH:84][CH:83]=5)[CH:75]=4)=[O:77])[CH2:56][CH2:55]3)=[C:50]([CH3:62])[C:49]=2[CH3:63])=[CH:44][CH:43]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(C(F)(F)F)n2)cc1
Reactant: CNC1CCN(c2nnc(-c3ccc(F)cc3)c(C)c2C)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(=O)N(C)C3CCN(c4nnc(-c5ccc(F)cc5)c(C)c4C)CC3)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Add PyBOP (343 mg, 0.65 mmol) and triethylamine (0.21 mL, 1.50 mmol) to a stirred solution of 1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-N-methylpiperidin-4-amine (157 mg, 0.50 mmol) and 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (165 mg, 0.55 mmol) in anhydrous DMF (2.5 mL). Stir the resulting mixture at ambient temperature under N2 overnight. Concentrate, add MeOH, filter solids, and concentrate the filtrate. Dilute the residue with MeOH, and pour onto an SCX column (Thermo Scientific, 10 g). Wash with MeOH, and then elute the product with 2 M NH3/MeOH. Concentrate and purify by flash silica gel chromatography using a gradient of 0 to 10% (10% 2 M NH3/MeOH in EtOAc) in hexanes to obtain the title compound as a white solid (170 mg, 43%). ES/MS m/z 597.0 (M+1).
Reaction SMILES: Cl.Cl.[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16](Cl)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:46]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1.C(Cl)Cl.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([N:34]4[CH2:38][CH2:37][C@@:36]5([C:46]6[CH:45]=[CH:44][N:43]=[CH:42][C:41]=6[C:40](=[O:47])[O:39]5)[CH2:35]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)C1(c2ccc(N3CCC3)nc2)CC1
Reactant: O=C1O[C@]2(CCNC2)c2ccncc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC5)nc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarbonyl chloride dihydrochloride (64.00 mg, 0.0002067 mol) and (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid—(1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (1:1) (87.3 mg, 0.000207 mol) in methylene chloride (1.00 mL, 0.0156 mol) was added N,N-diisopropylethylamine (0.144 mL, 0.000827 mol) at 0° C. The reaction mixture was stirred at rt for 1-2 h. Upon completion the reaction mixture was diluted with ethyl acetate and washed with water and brine successively, dried with sodium sulfate, filtered, and concentrated. The crude product was purified by prep-LCMS twice to obtain the product as a TFA salt. LCMS: m/z 391.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34]O)[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[N:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: OC[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Reactant: COc1ccc2ncc(C(=O)O)cc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-Methoxy-[1,5]naphthyridine-3-carboxylic acid (100 mg, 0.44 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol (129 mg, 0.44 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (93 mg, 0.48 mmol, 1.10 eq) and 4-(dimethylamino)pyridine (81 mg, 0.66 mmol, 1.50 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-[1,5]naphthyridine-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethyl ester as an off-white semisolid (33 mg, 15% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH2:21][CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH2:21][CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CCC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CCC
Yield: 44.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-propyl-1,3-oxazole-4-carboxylate obtained in Example (116c) (0.69 g, 2.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.22 g of the title compound as a colorless solid (44%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccccc1C
Temperature: 70 °C

Procedure:
A mixture of 10.8 g (0.1 mol) of o-cresol, 18.1 g (0.1 mol) of ethyl 2-bromopropionate, and 14.5 g of K2CO3 in 50 ml of DMF is heated at 70° C. for 3 days. The reaction mixture is poured into H2O, and extracted with ethyl acetate. The organic solution is dried and evaporated to give ethyl 2-(2-methylphenoxy)propionate which is used directly in the next step.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([O-:14])=O.O>CO.C(O)(=O)C>[OH:14][N:12]=[C:15]1[CH:20]=[CH:19][C:18](=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])[CH:17]=[C:16]1[CH3:21]
Reactant: N#CCc1ccccc1
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC1=CC(=C(C#N)c2ccccc2)C=CC1=NO
Temperature: 55 °C
Reaction time: 4 h

Procedure:
39.6 g of KOH (0.6 mol, assay 85%) are dissolved in 200 ml of methanol and heated up to 55° C. To the solution are added 23.4 g (0.20 mol) of phenylacetonitrile, followed by 25 g (0.18 mol) of o-nitrotoluene. The dark red reaction mixture is stirred at 55° C. for 4 hrs. After cooling, the mixture is poured into 500 ml of water, and acidified by addition of 60 ml of acetic acid. The resulting orange precipitate is filtered, washed with water, methanol:water 1:1 (v/v), and dried under vacuum. The crude product (16.8 g, 40%) has a melting point of 161-164° C. (dec) (Lit: 161° C. dec; J. Org. Chem. 26, 4270, 1961) and is used in the next step without further purification.
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([C@@H:11]([NH:27][C@H:28]1[CH2:34][S:33][C@H:32]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][N:30]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:29]1=[O:48])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(Cl)Cl.C(O)C>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:27][C@H:28]1[CH2:34][S:33][C@H:32]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][N:30]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:29]1=[O:48])[C:9]([O:8][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:10]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N[C@@H](CCCCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N[C@@H](CCCCN)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 46.2 %

Procedure:
0.6 ml of hydrazine monohydrate was added to a solution of 815 mg of t-butyl α-{6(R)-[1(S)-t-butoxycarbonyl-5-phthalimidopentylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 1) dissolved in a mixture of 3 ml of methylene chloride and 3 ml of ethanol, whilst ice-cooling, and the mixture was stirred at room temperature for 4 days. At the end of this time, the precipitate which appeared in the reaction mixture was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was mixed with ethyl acetate and the precipitated material was filtered off. The ethyl acetate filtrate was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure to remove the solvent. The residue was subjected to column chromatography through silica gel using mixtures of ethyl acetate and methanol in the proportions 10:1 and 4:1 by volume as the eluent to yield 302 mg of the title compound as syrup.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3.[CH:16]([C:18]1[C:19]([CH3:31])=[N:20][N:21]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:22]=1)=O>>[F:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:16][C:18]1[C:19]([CH3:31])=[N:20][N:21]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:22]=1)[CH2:9][CH2:8]3
Reactant: Fc1cc2c(s1)C1(CCNCC1)OCC2
Reactant: Cc1nn(-c2ncccc2C#N)cc1C=O
Product: Cc1nn(-c2ncccc2C#N)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Yield: 32 %

Procedure:
This compound is essentially prepared as described in Preparation 7 by using 2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] and 2-(4-formyl-3-methyl-pyrazol-1-yl)pyridine-3-carbonitrile. The residue is purified by SCX to give 2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbonitrile in a 32% yield. MS (m/z): 424 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:19]2[CH:20]([CH3:24])[NH:21][CH2:22][CH2:23][C:18]=2[S:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:18]4[S:17][CH:16]=[C:15]([F:14])[C:19]=4[CH:20]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2scc(F)c21
Product: CC1c2c(F)csc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9](O)[CH2:10][CH2:11][CH3:12].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCO
Reactant: Cc1cccc(N)c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCCCNc1cccc(C)c1
Yield: 80 %

Procedure:
214 parts of m-toluidine, 75 parts of n-butanol and 10 parts of triphenyl phosphite are heated for 10 hours at 230° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, the excess of m-toluidine and the unconverted butanol are distilled off under reduced pressure. 130 parts of N-butyl-m-toluidine, corresponding to a yield of 80% of theory, distil at a boiling point of 65° - 70° C/0.2 mm Hg.
Reaction SMILES: O.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:22]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: NCCCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 100 ml. of water and 120 ml. of tetrahydrofuran is added sequentially 12.4 g. of γ-aminobutyric acid, 10.4 g. of sodium bicarbonate, and 30 g. of N-benzyloxycarbonyloxysuccinimide. The reaction mixture is stirred for approximately 3.5 hours at room temperature and then the tetrahydrofuran is evaporated in vacuo. The residue is diluted with 200 ml. of water and extracted with (2×300 ml.) anhydrous ether. The aqueous layer is then acidified to pH 1-2 with 1 N hydrochloric acid and extracted with (3×400 ml.) methylene chloride. The methylene chloride extracts are collected and combined and then washed with (3×200 ml.) brine solution, dried with anhydrous magnesium sulfate and the solvent evaporated in vacuo at room temperature. The residue provides N-carbobenzoxy-γ-aminobutyric acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.[CH3:11][NH:12][CH:13](O)[CH3:14].[Na].C([OH:19])C>>[Cl:9][C:5]1[C:6]([Cl:8])=[N:7][C:2]2[O:19][CH2:14][CH2:13][N:12]([CH3:11])[C:3]=2[N:4]=1
Reactant: CCO
Reactant: CNC(C)O
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Agent: [Na]
Product: CN1CCOc2nc(Cl)c(Cl)nc21
Yield: 27 %

Procedure:
The crude product from the reaction of tetrachloropyrazine (10.8 g, 0.05 mol) and methylaminoethanol (3.7 g, 0.05 mol) in Example 1 above was dissolved in absolute ethanol and small pieces of sodium (1.2 g, 0.05 mol) were added. After stirring overnight the ethanol was evaporated and the solid residue was washed with water, filtered, and dried on a porous plate to a weight of 7 g. The solid was recrystallized from ethanol and isopropyl alcohol (IPA) to give 4 g (27% yield) of a white solid, m.p. 170°-2°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.C(O)C.CO>ClC1C=CC(Cl)=CC=1Cl>[O:9]=[C:10]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][CH:17]=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nccs1
Solvent: CCO
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: CCOC(=O)c1cnc2sccn2c1=O

Procedure:
A solution of 2-aminothiazole (10g., 100mM) and diethyl ethoxymethylenemalonate (21.6g., 100mM) in 1,2,4-trichlorobenzene (100ml) was heated at 150° C for 4 hours with collection of evolved ethanol. The reaction mixture was cooled and the required product filtered off and recrystallised from ethanol in 75.9% weight yield (17.0g). δ (CDCl3), 8.98 (1H,s, H5), 8.33 (1H,d, H1, J = 5.0Hz), 7.40 (1H,d, H2, J = 5.0Hz), 4.47 (2H,q, --CH2CH3), 1.41 (3H,t, --CH2CH3); λmax (MeOH) 235nm (εm 5000), 258nm (εm 4,550) and 346nm (εm 13,500); (Found: C, 47.84; H, 3,42; N, 12.19; S, 14.54%. C9H8N2O3S requires C, 48.22; H, 3.60; N, 12.50; S, 14.28%).
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:4]1)[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.O.C(OCC)(=O)C.O>[N:29]([C@H:7]1[C@@H:3]([CH2:1][CH3:2])[CH2:4][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Yield: 100.4 %

Procedure:
(3S,4R)-Benzyl 3-ethyl-4-(tosyloxy)pyrrolidine-1-carboxylate (21.25 g, 52.7 mmol) in DMF (50 mL) was added to a solution of sodium azide (8.56 g, 132 mmol) in DMF (50 mL) and water (30 mL) and heated to a bath temp. of 100° C. overnight. The reaction mixture was diluted with ethyl acetate/water and stirred. The organic layer was washed with water, dried (Na2SO4) and concentrated to give (3S,4S)-benzyl 3-azido-4-ethylpyrrolidine-1-carboxylate (14.5 g, 52.9 mmol, 100% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.34-7.41 (5H, m), 5.13-5.21 (2H, m), 4.08-4.11 (1H, m), LCMS: M+23=299, t=2.15 min.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:29](C)[CH:28]=[N:27][N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3].[CH3:32]C(O)C>ClCCl>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[NH:29][C:28]([CH3:32])=[N:27][N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:11])=[N:1][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nncn4C)ccc3C)csc12
Reactant: N
Reactant: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)[nH]4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a suspension of 4-chloro-3-[2-methyl-5-(methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.106 g; 0.24 mmol) (from Example 61 supra) in 2-propanol (20 mL) for 15-20 minutes. The mixture was then heated in a microwave reactor at 140° C. for 75 minutes. After cooling to room temperature the reaction mixture was diluted with dichloromethane (˜75 mL) and washed with water and then brine. The organic phase was dried (Na2SO4) and concentrated. The residue was triturated twice with hot dichloromethane to give 4-amino-3-[2-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 80.4 mg) Additional product was obtained by chromatographing the mother liquors from the two triturations. (Yield 7.7 mg, overall 82.49%).
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[C:12]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>C(O)C>[Cl:25][C:26]1[O:30][C:29]([CH:31]2[C:5]3=[C:6]4[N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10](=[O:19])[C:11]4=[C:12]([C:13]4[S:14][CH:15]=[C:16]([CH3:18])[N:17]=4)[N:4]3[CH2:3][CH:2]([CH2:23][OH:24])[O:1]2)=[CH:28][CH:27]=1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(O)CO)n1
Reactant: O=Cc1ccc(Cl)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CO)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 6-(2,3-dihydroxypropyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (450 mg, 1.284 mmol), 5-chlorofuran-2-carbaldehyde (184 mg, 1.413 mmol) and bismuth triflate (169 mg, 0.257 mmol) in ethanol (9.584 ml) was stirred at room temperature for 2.5 hours. TFA (310 μl) was added and the mixture heated under microwave radiation at 80° C. for 20 mins, then further heated under microwave radiation at 80° C. for 10 hours. The reaction was then concentrated to half-volume under vacuum, a further portion of bismuth triflate (169 mg, 0.257 mmol) and powdered molecular sieves (200 mg) were added and the mixture heated under microwave radiation at 80° C. for 10 hours. The mixture was evaporated under vacuum and the residue partitioned between EtOAc (100 ml) and saturated K2CO3(aq) (100 ml) The phases were separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-50% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:15][C:16]2[S:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[C:8](=[O:14])[N:9]=[C:10](SC)[N:11]=1)(=O)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:10]3[N:11]=[C:6]([CH2:5][OH:4])[N:7]([CH2:15][C:16]4[S:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)[C:8](=[O:14])[N:9]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CSc1nc(COC(C)=O)n(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(CO)n1Cc1ccc(C(F)(F)F)s1
Yield: 15 %

Procedure:
The synthesis was performed using [4-(methylthio)-6-oxo-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,6-dihydro-1,3,5-triazin-2-yl]methyl acetate synthesized in Reference Synthesis Example 330 and 1-(4-fluorophenyl)piperazine in a similar manner to Reference Synthesis Example 348 to obtain the title compound (yield: 15%) of Synthesis Example 458a and the title compound (yield: 65%) of Synthesis Example 458b.