Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:13]1[CH:15]([CH2:16][CH3:17])[CH2:14]1>[OH-].[Na+]>[CH2:1]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:14][CH:15]([OH:13])[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: CCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)CN(CC(=O)O)Cc1ccccc1

Procedure:
Obtained by reacting benzylglycine with 1,2-epoxybutane in 1N sodium hydroxide solution.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7]1)=[O:5])[CH3:2].[CH2:18](Br)[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[N:10]([CH2:18][CH3:19])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C)Oc2ccccc2NC1=O
Reactant: CCBr
Product: CCOC(=O)C1(C)Oc2ccccc2N(CC)C1=O

Procedure:
The title compound was prepared from ethyl-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-2-carboxylate and ethyl bromide according to the procedure described in Example 16. The title product was a viscous oil, which was purified by column chromatography (silica gel; dichloromethane/methanol 100:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4]/[C:3](=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])/[CH2:2]1.[NH3:13]>O1CCOCC1.CO>[NH2:13][C:3]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1
Reactant: CCOC(=O)/C=C1/CCCOC1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)CC1(N)CCCOC1
Temperature: 150 °C

Procedure:
Ethyl (2Z)-dihydro-2H-pyran-3(4H)-ylideneacetate (Preparation 37, 1.21 g, 7.11 mmol) was stirred in 1,4-dioxane (7 mL) in a microwave vial. A solution of 7M ammonia in methanol (5 mL) was added and the reaction heated for 3 hours at 150° C. in a Biotage Initiator™ microwave. A further solution of 7M ammonia in methanol (2 mL) was added and the reaction heated again for 2 hours at 150° C. in the microwave. The reaction was concentrated in vacuo and the residue dissolved in a further portion of 7M ammonia in methanol (10 mL) and heated for a further 5 hours at 150° C. in the microwave. The reaction was concentrated in vacuo to afford the title compound along with the methyl ester where trans-esterification had occurred. The material was used without further purification in the next step.
Reaction SMILES: [C:1]1([PH:7](=[O:14])[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.[CH:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH:15](/[P:7](=[O:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: C#CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCC/C=C/P(=O)(c1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
To 1 ml of toluene were added 1 mmol of diphenylphosphine oxide, 1 mmol of 1-octyne and 3 molar % of RhCl(PPh3)3 as a catalyst followed by subjecting to a reaction in a nitrogen atmosphere at room temperature for 1 hour. The reaction solution is concentrated and then isolated and purified by means of liquid chromatography to give [(E)-1-octen-1-yl]diphenylphosphine oxide in a yield of 70%.
Reaction SMILES: I[CH2:2][C:3]1([CH3:32])[CH2:7][C:6]2[C:8]([CH3:31])=[C:9]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:10]([CH3:22])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:5]=2[O:4]1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]2[C:5]3[O:4][C:3]([CH3:32])([CH2:2][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:7][C:6]=3[C:8]([CH3:31])=[C:9]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:10]=2[CH3:22])=[CH:18][CH:17]=1)([CH3:20])[CH3:21]
Reactant: C1CCNC1
Reactant: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(CI)O2
Solvent: O
Product: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(CN1CCCC1)O2
Yield: 95 %

Procedure:
A mixture of N-(2-(iodomethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (102 mg, 0.19 mmol) obtained in Example 336 and pyrrolidine (1.5 mL) was reacted using a microwave reactor (110° C., hold time 20 min, 250 W). Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 86 mg (yield: 95%) of the title compound. Melting point: 143-144° C. (THF-hexane).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([CH3:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:28]1\[C:23]([NH2:22])=[CH:24][C:25](=[O:30])[CH:26]=[C:27]\1[CH3:29]
Reactant: Cc1cc(N)cc(O)c1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=CC(=O)C=C(N)/C1=N\c1c(N)n2n(c1=O)CCC2

Procedure:
0.5 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-5-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: N[C@@H:2]([C:10](O)=O)[CH2:3]C1N=CC=CC=1.[NH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][CH:17]=1.N[C@@H](C(O)=O)CC1C=CN=CC=1>>[CH:3]1[CH:2]=[CH:10][C:19]2[NH:20][CH:21]=[C:16]([CH2:15][C@@H:14]([NH2:13])[C:22]([OH:24])=[O:23])[C:18]=2[CH:17]=1
Reactant: N[C@H](Cc1cccnc1)C(=O)O
Reactant: N[C@H](Cc1ccccn1)C(=O)O
Agent: N[C@H](Cc1ccncc1)C(=O)O
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
with at least one of position 3 or 6 being D-2-Pal, D-3-Pal, or D-4-Pal; and
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:28])[C:9]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:19][C:18]=2[CH:27]=1)=[CH:10][N:11]([CH3:13])C.Cl.[CH2:31](N)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH3:29])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:28])[C:9]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:19][C:18]=2[CH:27]=1)=[CH:10][NH:11][CH2:13][CH3:31]
Reactant: Cc1nsc(NC(=O)C(=CN(C)C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Reactant: CCN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC=C(C(=O)Nc1snc(C)c1Cl)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 60 °C
Yield: 85.4 %

Procedure:
A mixture of N-(4-chloro-3-methylisothiazol-5-yl)-α-[(dimethylamino)methylene]-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.20 g, 0.00046 mole) [from Example 5] and ethylamine hydrochloride (0.0225 g, 0.0028 mole) in tetrahydrofuran (4 ml) and water (1 ml) was heated for 24 hours at 60° C. The mixture was cooled to room temperature, the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Further purification by flash column chromatography, eluting with ethyl acetate:hexane at 2:3 by volume, gave N-(4-chloro-3-methylisothiazol-5-yl)-α-[(ethylamino)methylene]-[2-(2,2-dimeth-ylpropyl)benzoxazol-5-yl]acetamide as a colourless solid (0.17 g). Analysis by 1H NMR showed the product comprised a mixture of E- and Z-isomers.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:37](=[O:39])[CH3:38]>C1COCC1>[C:19]([CH:16]1[CH2:15][CH2:14][CH:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:37](=[O:39])[CH3:38])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3c2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (5 g, 0.01 mol) in 15 mL dry THF stirring at −78° C., was added 2.0 M of n-Butyllithium in hexane (8.3 mL, 0.017 mol) dropwise. The reaction was then stirred at −78° C. for 15 minutes, yellow color results. N-Methoxy-N-methyl-acetamide (1.6 mL, 0.015 mol) in 5 mL THF was then added dropwise while the reaction was stirred at −78° C. (r×n went colorless upon addition of B). Reaction was then quenched with water and extracted three times with ethyl ether. Organics were dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. Material was purified via column chromatography using a gradient of 0-10% EtOAC/Hexanes (ran neat hexanes for 5 min to elute desbromo SM) on 125 g of SiO2 to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[C-:22]=[N:21][N:20]=[N:19]1.[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:19]2[N:20]=[N:21][CH:22]=[N:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Reactant: [c-]1nnn[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(n3ncnn3)C2)cc1
Temperature: 87.5 °C
Yield: 19.2 %

Procedure:
A suspension of N-benzyl-3-[(methylsulphonyl)oxy]pyrrolidine (2.2 g, 9.37 mmol) and sodium 1,2,3,4-tetrazolide (1.8 g, 19.6 mmol) in 50 ml of dimethylformamide was heated at 85-90° C. overnight. The reaction mixture was worked up the same as described in Example U. The crude product was purified over silica gel using hexane, ether and ethyl acetate as eluant to afford in order of elution 0.413 g of N-benzyl-3-(1,2,3,4-tetrazol-2-yl) pyrrolidine as an oil. 1H NMR (CDCl3) δ: 8.51 (s, 1H), 7.37-7.17 (m, 5H), 5.51-5.35 (m, 1H), 3.8-3.65 (q, 2H), 3.3-2.4 (m, 6H); and.26 g of N-benzyl-3-(1,2,3,4-tetrazol-1-yl)pyrrolidine as an oil. 1H NMR (CDCl3) 6 : 8.88 (s, 1H), 7.4-7.2 (m, 5H), 5.35-5.2 (m, 1H), 3.83-3.6 (q, 2 H), 3.2-2.3 (m, 5H), 2.15-2.00 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[C:46]1([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]([C:37]4[CH:38]=[CH:39][C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:36]=4)([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccc3ccccc3c2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccc5ccccc5c4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl)-ethyl-methanesulfonate (5 mmol) and 4-(naphth-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)[C:5]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][N:3]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:33]=[CH:34][C:35]([NH:36][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=4)[C:5]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:4][N:3]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:31]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2ccccc2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2Nc2ccccc2)c1
Temperature: 200 °C

Procedure:
N-(3-(2-Chloro-5-(phenylamino)pyrimidin-4-yl)phenyl)acrylamide (30 mg, 0.086 mmol), 4-morpholinoaniline (15.24 mg, 0.086 mmol) and Cs2CO3 (33.4 mg, 0.103 mmol) were dissolved in toluene (4.5 mL) in a sealable microwave compatible reaction tube, then tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3; 1.566 mg, 1.710 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.979 mg, 3.42 μmol) were added. The reaction tube was sealed and the reaction was heated under microwave irradiation (30 min, 200° C., 3 atm). After completion of the reaction, solvent was removed by vacuum and product was purified by flash column chromatography. 1H NMR (400 MHz, CD3OD): δ 8.32 (s, 1H), 8.21 (s, 1H), 7.69-7.61 (m, 4H), 7.30 (t, 1H, J=8.0 Hz), 7.07 (m, 2H), 6.95 (m, 2H), 6.65 (m, 3H), 6.42-6.37 (m, 2H), 5.76 (dd, 1H, J=2.4 and 9.6 Hz), 3.82 (m, 4H), 3.08 (m, 4H); ESI-MS: [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:16][OH:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: NO
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccn1)c1ccccn1
Yield: 136.4 %

Procedure:
2 g of di-2-pyridyl-ketone and 1.51 g of hydroxylamine-hydrochloride are added to 13 ml of pyridine and the mixture is held at reflux for 4 hrs. After concentration and cooling there are isolated 2.95 g of crude di-2-pyridyl ketone oxime (contaminated with salts). Addition of 1.18 g of ammonium acetate, 44 ml of dil. ammonia, 30 ml of water and 30 ml of ethanol yields a suspension which is treated portionwise with 4.5 g of zinc powder. The mixture is held at reflux for 4 hrs., cooled and suction filtered. The filtrate is concentrated and the residue is triturated with methanol. 2.54 g of crude C,C-dipyridin-2-yl-methylamine are isolated. Yield: 93%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([Cl:9])[C:6]=1[C:7]#[N:8].OC1C=CSC=1.P(Cl)(Cl)(Cl)=O.OC1SC=CC=1.[CH3:29][N:30]([CH3:33])[CH:31]=O>>[Cl:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([N:1]=[CH:29][N:30]([CH3:33])[CH3:31])[S:3][C:4]=1[CH:10]=[O:11]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: CN(C)C=O
Agent: Oc1cccs1
Agent: Oc1ccsc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N

Procedure:
The intermediate N'-(4-chloro-3-cyano-5-formyl-2-thienyl)-N,N-dimethylformamidine (IV) ##STR4## is formed from the 4-hydroxythiophene derivative (III) by treatment with a mixture of N,N-dimethylformamide and phosphoryl chloride and then converted direct to 2-amino-4-chloro-3-cyano-5-formylthiophene by acid hydrolysis, without its having been isolated. For this it is expedient to dissolve the 4-hydroxythiophene derivative (III) in N,N-dimethylformamide and add phosphoryl chloride to the solution at a temperature of from 20° C. to 80° C.; the mole ratio of the hydroxythiophene to N,N-dimethylformamide to phosphoryl chloride is generally from 1:10:2 to 1:20:3. After a further period of from 2 h to 8 h, during which the solution is kept stirred at a temperature of from 20° C. to 80° C., the formamidine (IV) that is formed is subjected to acid hydrolysis, which is done conveniently by running the reaction mixture into water. After completion of the latter procedure (which is accompanied by a strongly exothermic reaction) the mixture is usually stirred at a temperature of from 80° C. to 100° C. for from 1 h to 4 h, during which time the required thiophene derivative (II) precipitates. The product is finally separated, washed, and dried.
Reaction SMILES: [NH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]1=S.O.[NH2:16][NH2:17]>>[NH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]1=[N:16][NH2:17]
Reactant: NN
Reactant: S=c1nnc2c([nH]1)[nH]c1ccccc12
Solvent: O
Product: NN=c1nnc2c([nH]1)[nH]c1ccccc12
Temperature: 120 °C

Procedure:
A solution of 1,9-Dihydro-1,3,4,9-tetraaza-fluorene-2-thione 14c (56 mmol, 1 equiv.) in hydrazine hydrate (195 mL) is heated to reflux (120° C.) for 4 hours as disclosed in Joshr, K. C.; Dandia, A.; Bawbia, S. J. Ind Chem. Soc. (1989), 66, 690-693 and references therein. The mixture is allowed to cool to room temperature for 48 hours. The orange-yellow precipitate is filtered, washed with water and ethanol, and dried under vacuum for 15 hours to yield (1,9-Dihydro-1,3,4,9-tetraaza-fluoren-2-ylidene)-hydrazine 14d as a yellow powder.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.CS(O[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)(=O)=O>O>[Cl:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][N:12]([C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:13])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CN[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 60 °C

Procedure:
(±)-cis-2-Pyrrolidinyl-N-methylcyclohexylamine (3 gm) was combined with anhydrous dimethylformamide (70 ml) and warmed to 60° C. 2-(3,4-dichlorophenyl)ethyl methanesulfonate (14 gm) was added to the warm amine solution over 3 days. The reaction mixture was diluted to 500 ml with water and extracted with chloroform. The combined extracts were washed with water and treated with a solution of hydrogen bromide in methanol. The solution was concentrated on a rotary evaporator and the residual dimethylformamide removed by distillation under high vacuum. The residue was triturated with 2-propanol to provide a white solid. The solid was recrystallized from 2-propanol. Analytical data are reported in Table I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:9]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]O)[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c2ccc(O)cc2c1=O
Reactant: OCc1cccnc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(-c2ccc(F)cc2)c2ccc(OCc3cccnc3)cc2c1=O
Temperature: 0 °C
Yield: 77.3 %

Procedure:
Compound L (15 mg, 0.048 mmol, 1.0 eq) and 3-pyridinemethanol (10 mg, 0.096 mmol, 2.0 eq) were dissolved in THF (0.5 mL) and cooled to 0° C. Triphenylphosphine (28 mg, 0.11 mmol, 2.2 eq) and di-tert-butylazodicarboxylate (18 mg, 0.077 mmol, 1.6 eq) were added and the reaction was stirred at room temperature until complete by LCMS. The reaction was concentrated and purified using reverse phase chromatography to afford 15 mg (77%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=1.7 Hz, 1H), 8.54 (dd, J=4.7, 1.3 Hz, 1H), 8.41 (s, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J=3.0 Hz, 1H), 7.73-7.70 (m, 2H), 7.50 (t, J=8.8 Hz, 2H), 7.43 (dd, J=7.8, 4.8 Hz, 1H), 7.37 (dd, J=9.3, 3.0 Hz, 1H) 6.94 (d, J=9.2 Hz, 1H), 5.28 (s, 2H), 3.72 (s, 3H); ES-MS [M+1]+: 405.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1.[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:17]([O:16][C:14]([NH:15][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Yield: 74.1 %

Procedure:
A flask was charged with ethyl 2-(2-chloropyridin-4-yl)acetate (20.00 g, 100.2 mmol), tert-butyl carbamate (35.21 g, 300.5 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.90 g, 5.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.29 g, 2.51 mmol), cesium carbonate (48.96 g, 150 mmol) and THF (400 mL). The mixture was heated at reflux under nitrogen for 24 hours. Upon cooling, the reaction was quenched with 10% ammonium acetate solution and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate/hexane to yield 20.80 g (72.6% yield) of the desired product as white solid.
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[N:8]=[CH:9][N:10]3[CH:14]=[CH:13][S:12][C:11]=23)C(=O)C2=CC=CC=C12.NN>>[NH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][C:11]=12
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncn2ccsc12
Agent: NN
Product: NCc1ncn2ccsc12

Procedure:
To a suspension of 0.379 g (1.34 mmole) of 7-(phthalimido)methylimidazo[5,1-b]thiazole in 15 ml of ehtanol was added 0.063 ml (2.0mmle) of anhydrous hydrazine, and the mixture was heated under reflux for 1 hour. The reaction mixture was ice-cooled, and the resulting crystalline products were removed by filtration. After the filtrate was concentrated under reduced pressure, a small amount of dichloromethane was added, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give crude 7-aminomethylimidazo[5,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][CH:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(O)Cc1ccc(N)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc(Nc2ccc(CC(C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and 1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:27]([NH2:29])[CH3:28]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[S:19][C:20]([C:23]([NH:29][O:27][CH3:28])=[O:25])=[CH:21][N:22]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)O)s3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1

Procedure:
2-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 227, 100 mg, 0.25 mmol) was reacted with methoxylamine hydrochloride according to procedure described in Example 8 to afford the title compound (30 mg).