Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1I)=[O:4].[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:19][N:18]([CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Reactant: CN(N)c1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NN(C)c1ccccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.28 mmol), N,N-diethylenediamine (9 μL, 0.086 mmol), N-methyl-N-pyridin-2-yl-hydrazine (0.105 g, 0.86 mmol), CuI (0.01 g, 0.057 mmol), 4 Å ms (0.114 mg) and K2CO3 (0.118 g, 0.861 mmol) in DMF (3 mL) was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate, washed twice with 5% LiCl, concentrated and the crude material was purified by silica gel chromatography (0-20% EtOH in DCM) to give 5-(3,3-dimethyl-but-1-ynyl)-3-(N′-methyl-N′-pyridin-2-yl-hydrazino)-thiophene-2-carboxylic acid methyl ester in 50% yield. This was then dissolved in pyridine (5 mL) and treated with neat trans-4-methyl-cyclohexanecarbonyl chloride (0.132 g, 0.825 mmol). The reaction was heated for 16 h at 85° C. and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was then dissolved in a 3:2:1 mixture of THF:MeOH:water (5 mL), treated with lithium hydroxide monohydrate (0.69 g, 1.65 mmol) and heated to 60° C. for 1 hour. The organic volatiles were evaporated under reduced pressure and the crude material was purified by HPLC to afford the title compound. MS (m/z): 454.1 [M+H]−; HPLC retention time: 3.95 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: N[C:2]1S[C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1C(OCC)=O.[C:14]([C:19]1[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:20]=1[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])([O:16][CH2:17][CH3:18])=[O:15].C(I)CCCCC>>[CH2:13]([N:26]([C:20]1[S:21][C:22]([CH2:24][CH3:25])=[CH:23][C:19]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH2:12][CH2:4][CH2:5][CH2:6][CH3:2]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: CCOC(=O)c1cc(CC)sc1NC(=O)C(C)C
Solvent: CCCCCCI
Product: CCCCCCN(C(=O)C(C)C)c1sc(CC)cc1C(=O)OCC

Procedure:
Ethyl 2-amino-5-ethyl-3-thiophenecarboxylate (Chemische Berichte 99, 94 (1966) )was converted into N-(3-carbethoxy-5-ethyl-2-thienyl)-2-methylpropanamide by the method described in Example 41. Alkylation of the unpurified product with n-hexyl iodide as described in Example 43 gave the title compound as a light yellow oil, b.p. 145°-147° C/0.25 mm. NMR showed that the material was the correct product.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[OH:3].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:2]([CH3:1])[O:3][C:25]2=[O:27])[CH2:16][CH2:15]1)([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: CC(O)c1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1OC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol from Step 2 above (1.9 g, 5.9 mmol) was stirred in dry THF in an ice bath under nitrogen, and triphosgene (0.59 g, 1.98 mmol) was added followed by triethylamine (2.5 ml, 1.8 g, 17.8 mmol). The ice bath was removed and the mixture was stirred at ambient temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with 1N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 1-(1-Boc-4-piperidyl)-4-methyl-3,1-benzoxazin-2-one.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[O:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:31])([CH3:32])[O:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2(C)C)cc1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (250 mg, 0.5 mol) in 1,4-Dioxane (10 mL) were added 4-methoxyphenylboronic acid (92 mg, 0.6 mol), Na2CO3 (127 mg, 1.5 mol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min followed by addition of Pd(PPh3)4 (58 mg, 0.05 mol) and then refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one- (40 mg, 18%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.41 (m, 1 H), 8.02-7.98 (m, 2 H), 7.78 (t, J=7.8 Hz, 1 H), 7.68-7.52 (m, 2 H), 7.25-7.21 (m, 4 H), 7.02-6.98 (m, 4 H), 5.40 (s, 2 H), 5.25 (s, 2 H), 3.79 (s, 3 H). MS: M+H: m/z=452.2; M+Na: m/z=474.3. HPLC: 91%, (Condition-B).
Reaction SMILES: [CH2:1]([C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:2][SH:3].[CH3:29][N:30]([CH3:40])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[C:36]([CH3:38])=[CH2:37].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[C:4]([CH2:1][CH2:2][S:3][CH2:38][CH:36]([C:35]([NH:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:40])[CH3:29])=[O:39])[CH3:37])([C:5]([C:6]([C:7]([C:8]([C:9]([C:10]([C:11]([F:14])([F:13])[F:12])([F:16])[F:15])([F:17])[F:18])([F:19])[F:20])([F:21])[F:22])([F:23])[F:24])([F:25])[F:26])([F:27])[F:28]
Reactant: C=C(C)C(=O)NCCCN(C)C
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: CC(CSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)NCCCN(C)C
Yield: 78.2 %

Procedure:
1,1,2,2-Tetrahydroperfluorodecanethiol (12.04 g, 0.025 mole), N-(3-dimethylaminopropyl)methacrylamide (3.88 g, 0.023 mole), and benzyltrimethylammonium hydroxide in methanol (4 drops) were heated overnight at 70° C. The resultant mixture was stripped of volatiles and distilled at 150°/≠0.1 mm Hg to yield 11.7 g of pale-yellow liquid (78.1% theory) which subsequently crystallized to a solid, m.p. 47°-50° C. NMR showed proton resonances at δ1.05, 3 protons, CH CH3 ; δ1.55, 2 protons, NHCH2CH2CH2N(CH3)2 ; δ2.10, 6 protons, 2 × NCH3 ; δ2.00-δ2.80, 10 protons, CF2CH2CH2SCH2 + NHCH2CH2CH2N; δ3.05; 1 proton, CH(CH3)CO; δ7.50, 1 proton, NH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.O.F[B-](F)(F)F.[O:23]=[N+:24]=[O:25]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[C:6]([N+:24]([O-:25])=[O:23])[CH:7]=1
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(NCCc1ccc(Br)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To a stirred solution of 23.89 g of N-[2-(4-bromophenyl)ethyl]-2,2,2-trifluoroacetamide in 200 mL of acetonitrile was added in one portion 13.87 g of nitronium tetrafluoroborate under ice-cooling. After the mixture was stirred at room temperature for 15 minutes, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 11.03 g of N-[2-(4-bromo-2-nitrophenyl)ethyl]-2,2,2-trifluoroacetamide.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[F:52][C:53]([F:67])([F:66])[C:54]1[C:55]([NH2:65])=[C:56]([NH2:64])[CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1>>[F:52][C:53]([F:66])([F:67])[C:54]1[C:55]2[N:65]=[C:44]([C:40]3[C:39]([NH:38][C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:50][CH:49]=[CH:48][C:47]=4[F:51])=[CH:43][NH:42][N:41]=3)[NH:64][C:56]=2[CH:57]=[C:58]([C:60]([F:61])([F:62])[F:63])[CH:59]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1)c1c(F)cccc1F

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 3,5-bis(trifluoromethyl)-1,2-diaminobenzene to give N-[3-(4,6-bis-trifluoromethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (51 mg) as a pink solid. (LC/MS: Rt 3.64, [M+H]+ 476.07).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[CH:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)ccc1Cl
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)c(C)c3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BN) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 456.0938 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=O)[O:28]C4C=CC=CC=4)[N:21]=3)[C:12]2=[O:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH:38][CH3:39]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[N:38]([CH3:39])[CH3:37])[N:21]=3)[C:12]2=[O:36])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)Oc4ccccc4)n3)C(C)(C)C2=O)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1nccc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 70 mg of phenyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyrimidin-2-yl)carbamate obtained in stage a) below in 3 mL of tetrahydrofuran is introduced, under argon, 0.71 mL of a 2M solution of dimethylamine in tetrahydrofuran. After stirring for one hour at room temperature, the reaction medium is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a dichloromethane/acetonitrile/methanol mixture (98/1/1 by volume) to give 20 mg of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyrimidin-2-yl)-1,1-dimethylurea in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26]O.[OH-].[K+]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:23]3[CH2:24][CH2:25][CH2:26][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCCN12
Yield: 104.6 %

Procedure:
To a suspension of 11.3 g of 2-trichloroacetamido-5-chlorobenzophenone in 100 ml. of ethanol was added 4.51 g of 3-amino-1-propanol. The mixture was heated under reflux for 3 hours. Then, 1.7 g of potassium hydroxide was added thereto and the resulting mixture was further refluxed for 3 hours. After cooling, the precipitate was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure and to the residue was added 200 ml. of water. The resulting solid was collected by filtration, washed with water and dried to give 9.87 g of 10-chloro-3,4,7,11b-tetrahydro-11b-phenyl-2H,6H-[1,3]oxazino[3,2-C]quinazolin-6-one. Recrystallization from ethanol gave pale yellow prisms, having a melting point of 202°-203.5°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]=1[C:8]#[N:9].[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:23][CH2:22]1)(=O)[CH3:19]>>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:6]1[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=[C:2]([N:1]=[C:18]([N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:23][CH2:22]2)[CH3:19])[C:7]=1[C:8]#[N:9]
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 95 %

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-(2,2,2-trifluoroethoxy)-anisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following a similar procedure to that described in Example 10(g) allowing the reaction to stir for 60 hours at room temperature. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 to 95:5, v/v). The product was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered off and partitioned between saturated aqueous sodium hydroxide solution (100 ml) and dichloromethane (200 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound (1.83 g, 95%). Rf 0.58 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 484 (MH)+.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=O)[NH:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:19])[NH:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NS(=O)(=O)c2cscc21
Solvent: c1ccncc1
Solvent: O
Product: O=S1(=O)NC(=S)c2cscc21
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 40 %

Procedure:
To a mixture of 5.6 g. (0.03 mole) of thieno[3,4-d]isothiazol-3(2H)-one-1,1-dioxide in 50 ml. of dry pyridine is added 5.6 g. (0.016 mole) of phosphorus pentasulfide portionwise over 3 minutes. The viscous mixture is slowly heated in an oil bath under an atmosphere of nitrogen. The temperature of the oil bath is slowly increased to 80° C. after 30 minutes. The temperature of the oil bath is then kept at 80° C. for 25 minutes, the internal temperature reading 63° C. The solution is cooled to 50° C. and is added dropwise over 5 minutes to 200 ml. of water and cooled in an ice bath. The precipitate which forms is collected and discarded. The filtrate is cooled in ice and acidified with concentrated hydrochloric acid to pH 1. The precipitate which forms is collected to yield 40% of material. In another experiment, a sample is recrystallized from water to obtain an analytical sample, m.p. 196°-8° (dec.).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([N:35](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:35][CH3:33])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.013 g (0.20 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with hexane-ethylactate (gradient, 50:50-0:100) gave 0.062 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-24) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=2)[CH2:17][CH2:16]1.ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:23][C:21]2[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[CH:22]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(C2CC2)nn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C3CC3)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 35 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.061 g, 0.26 mmol) and 3-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.05 g, 0.20 mmol) in pyridine (1 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.031 g, 0.070 mmol, 35%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=4.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.55-7.51 (m, 5H), 7.41 (s, 1H), 7.39 (s, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.12 (s, 1H), 1.99-1.93 (m, 1H), 1.36 (s, 9H), 1.01-0.92 (m, 2H), 0.84-0.79 (m, 2H); MS: (ES) m/z calculated for C25H27N4O2S [M+H]+ 447.2. found 447.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(C)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(C)cc1)OCC

Procedure:
A solution of 6.5 g of ethyl 2-(4-methylphenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methylphenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.6 ppm (CDCl3).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12](OC)=[O:13])=[CH:5][CH:4]=1)#[N:2].B([O-])=O.[Na+].[OH-].[Na+]>C1COCC1.CO>[OH:13][CH2:12][C:11]1[CH:10]=[C:9]([CH:18]=[CH:17][CH:16]=1)[CH2:8][O:7][C:6]1[CH:19]=[CH:20][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccc(COc2ccc(C#N)cc2)c1
Agent: O=B[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(OCc2cccc(CO)c2)cc1
Temperature: 62 °C
Reaction time: 5 h

Procedure:
20.05 kg (26.7 mol) of methyl 3-(4-cyano-phenoxymethyl)-benzoate are dissolved in 100 liters of THF and 40 liters of methanol. At 40 to 45° C., 8.51 kg of sodium boranate are added in batches. The reaction is completed by stirring the reaction mixture at 61 to 63° C. for about 5 hours. The reaction mixture is then cooled to 25° C. and 90 liters of a 15% sodium hydroxide solution are added. After stirring, the aqueous supernatant is separated off and mixed with 30 liters of a 22.5% sodium hydroxide solution. After stirring, the aqueous supernatant is separated off and from this about 100 liters of solvent are distilled off at a sump temperature of 63 to 75° C. The distillation residue is crystallised by the addition of 20 liters of isopropanol at 50 to 60° C. and 150 liters of water at 40 to 50° C. After the suspension has been cooled to 20 to 30° C. the crystals are separated off, washed with 60 to 100 liters of water and batchwise with 25 liters of cold isopropanol and dried in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[OH-].[Na+]>[C:7]1([S:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Yield: 95 %

Procedure:
N-benzenesulfonylalanine was prepared by mixing equimolar quantities of alanine and benzenesulfonyl chloride at 60° C. in aqueous sodium hydroxide (200 mol%). A 95% yield was obtained. The method is set out in the previously mentioned book "Chemistry Of The Amino Acids".