Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[N:3]=1.I.[F:15][C:16]([F:24])([F:23])[CH2:17][NH:18][C:19](=[NH:22])SC.C(Cl)(Cl)Cl.CO.N>>[F:15][C:16]([F:24])([F:23])[CH2:17][N:18]=[C:19]([NH2:22])[NH:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[N:3]=1
Reactant: NC(=O)CCCCn1ccc(N)n1
Reactant: CSC(=N)NCC(F)(F)F
Agent: I
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 5-(3-aminopyrazol-1-yl]valeramide (18.2 mg.) and (2,2,2-trifluoroethyl)-S-methylisothiourea hydroiodide (51 mg.) was heated at 100° for 20 minutes. Preparative high pressure liquid chromatography on silica gel, using CHCl3 /MeOH/ammonia (s.g. 0.880) 8:2:0.5 v/v/v as eluant gave 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p. 129°-130° (40%).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[F:8][CH:9]([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>O>[F:8][CH:9]([F:17])[C:10]1[CH:11]=[C:12]([NH:13][C:1]2[CH2:5][CH2:4][C:3](=[O:6])[CH:2]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)C1
Reactant: Nc1cccc(C(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: O
Product: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclopentane-1,3-dione (2.00 g, 20.4 mmol), 3-(difluoromethyl)aniline (2.92 g, 20.4 mmol) and Ytterbium(III) trifluormethanesulfonate (63 mg, 0.10 mmol, 0.5 mol %) is stirred at room temperature for 2 h. Methanol and water are added and the resulting precipitate is filtered and dried. Yield: 2.75 g; ESI mass spectrum: [M+H]+=224; Retention time HPLC: 0.82 min (V012_S01).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:50][CH2:51][CH3:52])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:62][C:63]1[O:64][C:65](=[O:69])[O:66][C:67]=1[CH3:68]>CC(C)=O.C1(C)C=CC=CC=1>[CH3:52][CH2:51][CH2:50][C:7]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[N:30]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:29]=[N:28][N:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:9]([C:10]([O:12][CH2:68][C:67]2[O:66][C:65](=[O:69])[O:64][C:63]=2[CH3:62])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(=O)oc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
4-(1-Hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid dehydrate (100 g) was suspended in acetone (1 L) & heated to reflux; the solution obtained was added to suspension of potassium carbonate (15 g), potassium iodide (6 g) & 4-chloromethyl-5-methyl-1,3-dioxol-2-one (35 g) in acetone (500 mL) at reflux temperature. Reaction mass was refluxed for 2-6 hrs. After competition of reaction, the reaction mass was filtered & the acetone was distilled from combined mother liquor. The residue obtained was dissolved in toluene (1 L) toluene layer was washed with brine (3×250 mL). Toluene was removed under reduced pressure & residue thus obtained was recrystallized from methanol to give trityl Olmesartan
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24]C3C=CN=CC=3F)[C:5]2=[N:6][CH:7]=1.[CH2:32]([C:35]([F:38])([F:37])[F:36])[CH2:33][NH2:34]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH:34][CH2:33][CH2:32][C:35]([F:38])([F:37])[F:36])[C:14]4[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][N:6]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccncc4F)c4ncc(F)cc34)nc(I)c21
Reactant: NCCC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(NCCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
150 mg (0.186 mmol, approx. 66% purity) of the compound obtained in example 28A was dissolved in 1-methyl-2-pyrrolidone (3.6 ml) in a reaction vessel suitable for a microwave and 0.9 ml of 3,3,3-trifluoropropyl-1-amine was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 33 mg of the title compound was obtained (34% of theor.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]4[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]4)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Temperature: 95 °C
Reaction time: 120 h
Yield: 112 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (100 mg, 0.31 mmol) in 1.6 ml of NMP was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (200 mg, 1 mmol) and DIPEA (70 μL, 0.4 mmol). The reaction solution was stirred at 95° C. for 5 days. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl 3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (160 mg) as TFA salt. ES/MS m/z 461.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1cscc1OC
Reactant: CCCCCCC(O)CO
Product: CCCCCCC1COc2cscc2O1

Procedure:
Racemic 2-n-hexyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with racemic 1,2-octanediol as described in EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited no optical rotation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1cccs1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in example 7. MS(m/e): 429(M+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([CH:29]1[CH2:34][CH2:33][CH:32](OS(C)(=O)=O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC(=O)CC>CC(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:32]3[CH2:33][CH2:34][CH:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc2C1
Yield: 58.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g, 4.4 mmol), cesium carbonate (4.3 g, 13 mmol), and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2 g, 8.8 mmol). in t-BuOH (12 mL) and 2-butanone (6.0 mL) was heated in a sealed vial at 100° C. overnight. The mixture was partitioned between water and ether. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give white precipitate (1.0 g, yield: 58%). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 4.49 (s, 2H), 4.07 (m, 1H), 3.61 (s, 2H), 2.78 (m, 2H), 2.18 (d, 2H), 1.85 (d, 2H), 1.48 (s, 9H), 1.37 (m, 2H), 1.18-1.00 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: C(O[C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[F:6])C.C([Li])CCC.[NH2:21][C:22]1[C:27]([CH:28]=O)=[CH:26][N:25]=[C:24]([S:30][CH3:31])[N:23]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:6][C:5]1[C:4](=[O:15])[NH:21][C:22]2[N:23]=[C:24]([S:30][CH3:31])[N:25]=[CH:26][C:27]=2[CH:28]=1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CSc1ncc(C=O)c(N)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc2cc(F)c(=O)[nH]c2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 1.74 g (10.33 mmol) of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester in 20 mL of tetrahydrofuran is cooled to −78° C. and treated dropwise with 12.9 mL (20.65 mmol) of a 1.6 M solution of n-butyl lithium in hexanes. After stirring for 30 minutes at −78° C. the solution is treated with 1.74 g (10.33 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3), allowed to warm to room temperature, and stirred overnight. The reaction is treated with saturated aqueous ammonium chloride, then water. The solid is collected by filtration and washed with diethyl ether to give 2.01 g (92%) of the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:5](=[O:6])[N:4]([CH:7]2[CH:14]3[CH2:15][C:10]4([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]2[CH2:9]4)[CH2:13]3)[NH:3]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:5](=[O:6])[N:4]1[CH:7]1[CH:8]2[CH2:9][C:10]3([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:13][CH:14]1[CH2:15]3)[CH2:16]2
Reactant: COC(=O)C12CC3CC(C1)C(N1NC(C)(C)C1=O)C(C3)C2
Reactant: Clc1ccccc1CBr
Product: COC(=O)C12CC3CC(C1)C(N1C(=O)C(C)(C)N1Cc1ccccc1Cl)C(C3)C2

Procedure:
Methyl 4-(3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl)adamantane-1-carboxylate prepared in Process 5 of Example 90, and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and methyl 4-[2-(2-chlorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylate was obtained as a pale yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[C:9]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:8]1=2)=[O:6])([CH3:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[NH2:56][NH2:57]>CCO>[F:35][C:32]([F:34])([F:33])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[CH2:21][N:14]([C:15]1[CH:16]=[C:17]([CH3:18])[NH:57][N:56]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C:8]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:9]1=2
Reactant: NN
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3cc(Cl)ccc32)n[nH]1
Temperature: 0 °C
Yield: 21.2 %

Procedure:
Add cold (ice bath) absolute EtOH (1 mL) slowly to a cooled 0° C. stirred mixture of (+/−)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (118 mg, 0.20 mmol) and phosphorus pentoxide (511 mg, 3.6 mmol). Then, add hydrazine hydrate (0.062 mL, 2.0 mmol) dropwise while keeping the mixture cooled at 0° C. Heat at 100° C. overnight in a sealed tube. Cool down the mixture and remove the solvents under reduce pressure. Partition the residue between water and dichloromethane. Separate the layers, and dry organic phase over anhydrous magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, and then by a SCX cartridge to afford the title compound (25 mg, 21%). MS (ES+): 589 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>O>[CH3:1][C:2]1([CH3:15])[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: CC1(C)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Oc2cc3nc(SCc4ccccn4)[nH]c3cc2O1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 4.45 g of 2,2-dimethyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 100 ml of alcohol, were added dropwise while stirring 1.63 g of sodium hydroxide in 50 ml of water and, after 30 minutes, there were added 3.4 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of 3 N sodium hydroxide, three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from acetontrile. There were obtained 4.6 g (73.4% of theory) of 2,2-dimethyl-6-[(2-pyridyl-methyl)thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 210°-211° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:13][OH:14])[NH:8]CCOC)=[N:4][O:5][N:6]=1.O.[OH-].[K+].[C:18]([O:21][CH2:22]C)(=O)[CH3:19]>CCCCCC>[OH:14][N:13]=[C:7]([C:3]1[C:2]([NH:1][CH2:19][CH2:18][O:21][CH3:22])=[N:6][O:5][N:4]=1)[NH2:8]
Reactant: COCCNC(=NO)c1nonc1N
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: COCCNc1nonc1C(N)=NO
Temperature: 100 °C
Yield: 81 %

Procedure:
4-Amino-N′-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carboximidamide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed at 100° C. overnight (15 hours). TLC with 50% ethyl acetate (containing 1% ammonium hydroxide) in hexane indicated reaction completed (product Rf=0.6, starting material Rf=0.5). LCMS also indicated reaction completion. The reaction was cooled to room temperature and extracted with ethyl acetate (3×1 L). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (201 g, 81%) as a crude off-white solid. LCMS for C6H12N5O3 (M+H)+: m/z=202.3 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 6.22 (s, 2H), 6.15 (t, J=5.8 Hz, 1H), 3.45 (t, J=5.3 Hz, 2H), 3.35 (m, 2H), 3.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([NH:16][C:17](=[O:34])[CH:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:19][CH3:20])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH2:37][CH2:38]Br.C(=O)([O-])[O-].[K+].[K+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:35])[CH:4]([N:16]1[CH2:38][CH2:37][N:21]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH:18]([CH2:19][CH3:20])[C:17]1=[O:34])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCBr
Reactant: CCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 98 %

Procedure:
To a solution of 3-naphthalen-2-yl-2-[2-(2-nitrobenzenesulfonylamino)-butyryl amino]-propionic acid methyl ester, 31, (26.6 g, 53.2 mmol) in anhydrous DMF (100 mL) is added 1,2-dibromoethane (100.0 g, 532.0 mmol) and potassium carbonate (66.1 g, 479.0 mmol). The reaction mixture is heated at 60° C. over night. The reaction mixture is cooled in an ice bath and the pH is adjusted to ˜3 with 1M KHSO4. The reaction mixture is extracted with EtOAc (3×300 mL). The organic layers are combined and washed with water (200 mL), dried over Na2SO4 and concentrated in vacuo and the resulting residue is purified over silica (Hexane: EtOAc 1:1; 5% MeOH in EtOAc) to afford 27.4 g (98% yield) of the desired product. 1H NMR (CDCl3, δ): 8.02–7.90 (m, 1H), 7.84–7.70 (m, 3H), 7.64–7.58 (m, 3H), 7.55–7.50 (m, 1H), 7.50–7.40 (m, 2H), 7.30 (d, J=6.0 Hz, 1H), 5.35 (dd, J−12.0, 4.8 Hz, 1H), 4.25 (t, J=7.2 Hz, 1H, 3.78–3.68 (m, 1H), 3.65 (s, 3H), 3.52 (dd, J=15.0, 6.0 Hz, 1H), 3.30–3.10 (m, 4H), 1.58–1.50 (m, 1H), 1.42–1.38 (m, 1H), 0.56 (t, J=7.2 Hz, 3H); 13C NMR, δ 170.5, 167.8, 148.0, 134.2, 134.0, 133.6, 133.1, 132.6, 132.3, 130.9, 128.5, 127.9, 127.7, 127.5, 126.9, 126.5, 126.0, 124.6.
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O:17][C:18](=O)[CH:19]([CH3:25])[C:20](OCC)=[O:21])C.Cl>C(O)C>[CH3:25][C:19]1[C:20]([OH:21])=[N:13][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:14][C:18]=1[OH:17]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(-c2ccccc2)nc1O
Temperature: 40 °C
Reaction time: 22 h

Procedure:
To ethanol (180 ml) was added sodium ethoxide solution (38 ml of a 21% wt solution in ethanol), benzamidine hydrochloride (5.0 g) and diethylmethylmalonate (4.91 ml). The suspension was stirred at 40° C. in an inert atmosphere for 22 hrs after which time it was cooled to 5° C. (ice bath) and treated dropwise with concentrated hydrochloric acid to a pH of 2.5. The resulting pink suspension was filtered and washed with excess water. Purification by recrystallisation from boiling acetic acid (300 ml) afforded the title compound (4.22 g) after filtration and washing with ethanol (20 ml) and diethyl ether (20 ml).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:31][NH:32][CH3:33]>CO>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:32]([CH3:33])[CH3:31])[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CNC
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Solvent: CO
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N(C)C
Yield: 34 %

Procedure:
N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and dimethylamine in methanol (2M, 3 mL) were heated in a sealed React-vial at 120° C. for 24 hours. The cooled solution was evaporated to dryness in vacuo and the residue chromatographed over flash silica eluting with ethyl acetate (3× column lengths) followed by ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 44 (150 mg, 34%) as a white solid. TLC (SiO2, ethyl acetate: methanol: ammonia, 100:10:1) Rf=0.15 (UV detection, Dragendorff's reagent). LC: 100%. MS: m/z=490.3, 491.2 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.14 (1H, s), 8.07 (1H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 7.70 (1H, t, J=8 Hz), 4.74 (1H, d, J=12 Hz), 4.07 (1H, m), 3.95 (1H, d, J=12 Hz), 3.05 (2H, m), 2.50 (2H, m), 2.24 (6H, s), 2.15 (1H, 2d), 1.96 (1H, m), 1.86-1.69 (3H, m), 1.58-1.24 (6H, m), 0.98 (1H, m), 0.90 (3H, t, J=8 Hz), 0.87-0.75 (3H, m).
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=CC=1)(O)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:11]([N:12]([CH2:29][C:30]1[CH:31]=[CH:32][C:23]([CH2:14][CH2:13][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:24][CH:25]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[C@@H:23]1[CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=2[CH2:24]1)[CH3:10]
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Reactant: C1CCNC1
Product: CCN(Cc1ccc(CCN2CCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 43.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and pyrrolidine (12 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.8 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(#N)C>[C:41]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:42])[NH2:40]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(C(N)=O)C1
Reaction time: 4 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) in acetonitrile (1 mL) was added Et3N (79 μL, 0.79 mmol) followed by 85% trimethylsilyl isocyanate (125 μL, 0.784 mmol). After 4 hours, the cloudy mixture was filtered and attempts to crystallize the solid proved unsuccessful. The solid and filtrate was combined and diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a white solid.