Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[CH2:35]Br.C([O-])([O-])=O.[K+].[K+].N#N>CC#N>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[CH2:35][N:13]([S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(C1CCCc2cccnc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 51.9 %

Procedure:
To a solution of 2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide (3.72 g, 11.0 mmol) dissolved in CH3CN (120 mL) was added 2-bromomethyl-5-cyano-benzoic acid methyl ester (2.79 g, 11.0 mmol) and K2CO3 (4.56 g, 33.0 mmol). The mixture was stirred for 18 hours at 80° C. under a positive pressure of N2. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (150 mL). Brine (150 mL) was added and the mixture was extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a black oil. Purification via column chromatography on silica gel (hexanes:EtOAc, 2:1, v/v) afforded 5-cyano-2-{[(2-nitro-benzenesulfonyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}-methyl}-benzoic acid methyl ester as a yellow solid (2.89 g, 52%). 1H NMR (CDCl3) δ 1.55 (m, 1H), 1.89 (m, 2H), 2.34 (m, 1H), 2.66 (m, 2H), 4.44 (d, 1H, J=18.9 Hz), 5.18 (d, 1H, J=18.9 Hz), 5.38 (m, 1H), 6.98 (dd, 1H, J=7.5, 4.8 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.75 (m, 4H), 7.91 (d, 1H, J=4.4 Hz), 8.12 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH:26](O)([CH3:28])[CH3:27]>ClCC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:26]([CH3:28])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: CC(C)O
Agent: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Reaction time: 72 h
Yield: 67 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (240 mg, 0.78 mmol) and sodium bicarbonate (131 mg, 1.56 mmol) in isopropanol (20 mL), excess chloroacetone (1.5 mL) was added. After heating to reflux, the reaction mixture for 72 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (370 mg) was chromatographed (silica gel, hexane/ethyl acetate, 25/75) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole (160 mg, 67%): mp (DSC) 166° C. Anal Calc'd. for C17H15N2SO2Cl C, 58.87, H, 4.36, N, 8.08 Found: C, 58.78, H, 4.62, N, 7.99.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH2:32][CH2:33]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:24]1[CH2:32][CH2:33][N:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCC2Cc3ccccc3C2)C1

Procedure:
The title compound, MS: m/e=372.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and toluene-4-sulfonic acid 2-indan-2-yl-ethyl ester. Toluene-4-sulfonic acid 2-indan-2-yl-ethyl ester is a known compound and has been prepared as described in U.S. Pat. No. 3,984,407.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C[O:8][C:9]([C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)=[O:10].[OH:18][C:19]([CH3:52])([CH3:51])[CH2:20][C@@:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:26][C:25](=[O:27])[N:24]([C@H:28]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH3:29])[CH2:23][CH2:22]1>CN(C)C=O>[OH:18][C:19]([CH3:51])([CH3:52])[CH2:20][C@@:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:26][C:25](=[O:27])[N:24]([C@H:28]([C:30]2[CH:31]=[CH:32][C:33]([C:14]3[N:13]=[N:12][C:11]([C:9]([OH:8])=[O:10])=[CH:16][CH:15]=3)=[CH:34][CH:35]=2)[CH3:29])[CH2:23][CH2:22]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (1.46 mL) was added to a mixture of 6-chloropyridazine-3-carboxylic acid methyl ester (0.38 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.70 g) in N,N-dimethylformamide (8 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) dichloromethane complex (72 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling the mixture to ambient temperature, water and 1 M hydrochloric acid were added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/F3CCO2H) to afford the title compound as an oil that solidifies while standing. Yield: 0.36 g (52% of theory); Mass spectrum (ESI−): m/z=474 [M−H]−.
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NNC=2C=C[CH:4]=1.CN1CCOCC1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[C:35]([OH:37])=O)(=[O:28])=[O:27])=[CH:22][CH:21]=1.NC(C)CO>C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[C:35]([NH:10][CH2:11][CH:3]([OH:2])[CH3:4])=[O:37])(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CC(N)CO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Hydroxybenzotriazole hydrate (297 mg), (3-dimethylminopropyl)-3-ethylcarbodiimide (421 mg) and N-methylmorpholine (241 ml) were added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (575 mg) [see Preparation 38]. The reaction mixture was stirred for 15 mins, then 2-aminopropanol (170 ml) was added and stirring continued for 18 hrs at room temperature. The mixture was then diluted with ethyl acetate and washed with 2M aqueous hydrochloric acid, saturated sodium hydrogen carbonate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-hydroxypropyl)-2-piperidinecarboxamide (555 mg) as an oil.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Boc--L--Leucine methyl ester (22.7 g, 90 mmoles) in dry toluene (250 ml) under N2 was cooled to -78° and 25% di-isobutylaluminium hydride in toluene (130 ml, 225 mmoles) were added over 25 mins. keeping the temperature under -70°. The mixture was stirred for 15 mins. at -78° after completion of the addition, then MeOH (10 ml) was added cautiously. When effervescence ceased the mixture was poured into an ice-cold solution of Rochelle salt (100 ml of saturated solution+600 ml H2O). This mixture was shaken until an extractable solution was obtained. The toluene was separated and the aqueous phase re-extracted with ether (2×300 ml). Toluene and ether extracts were combined and dried (Na2SO4). The resulting oil was passed rapidly through a pad of silica gel in 15% EtOAc/petrol 40°-60°. The crude aldehyde was obtained as an oil, weight 18.68 g. Nmr showed aldehyde content to be 85%, therefore yield of aldehyde: 15.9 g (83%).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[S:16][C:15]([C:17]([NH2:19])=[O:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[O:23]1[CH2:28]CC(CCN)C[CH2:24]1.[BH4-].[Na+]>CO>[O:23]1[CH2:28][CH2:22][CH:2]([CH2:3][CH2:4][NH:5][CH2:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[CH:14][CH:13]=3)=[CH:9][CH:8]=2)[CH2:1][CH2:24]1
Reactant: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)s2)cc1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2)s1
Reaction time: 8 h

Procedure:
Place 5-(4-formylphenoxy)thiophene-2-carboxamide (Example 10, Part C) (0.235 g, 0.948 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.122 g, 0.996 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.7 mL), cap and stir overnight. Add NaBH4 (0.0359 g, 0.948 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 30% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C19H25N2O3S 361.1586 (M+H)+, found 361.1604, time 0.36 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.4 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.OS(O)(=O)=O.O=S(=O)=O.[N+:19]([O-])([OH:21])=[O:20].C(=O)([O-])[O-].[NH4+].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cc1ccc(Cl)c[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1cc([N+](=O)[O-])c(Cl)c[n+]1[O-]
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-methylpyridine-N-oxide (9.46 g) in concentrated sulphuric acid (30 ml), a nitration mixture consisting of 30% oleum (28 ml) and fuming nitric acid (47 ml), was added dropwise at 5°-8° over 20 minutes. The reaction mixture was allowed to stand for one hour at room temperature and then heated for 2 hours on a steam bath After allowing to cool the solution was poured onto ice and carefully neutralised with ammonium carbonate, added in portions. The solid was extracted into chloroform, dried, stripped and triturated with petrol to give 5-chloro-4-nitro-2-methylpyridine-N-oxide, (9.83 g), m.p.120°-122°
Reaction SMILES: C([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N:26]4[CH:30]=[N:29][N:28]=[CH:27]4)[CH:24]=3)[NH:19][CH:18]=2)[CH2:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N:26]4[CH:27]=[N:28][N:29]=[CH:30]4)[CH:24]=3)[NH:19][CH:18]=2)[CH2:11]1
Reactant: c1ccc(CNC[C@@H]2CCN(CCc3c[nH]c4ccc(-n5cnnc5)cc34)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC[C@@H]1CCN(CCc2c[nH]c3ccc(-n4cnnc4)cc23)C1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of (3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)ethyl]pyrrolidine (Example 7; 0.277 g, 0.639 mmol), ammonium formate (0.218 g, 3.46 mmol) and 10% Pd-C (0.28 g), in anhydrous methanol (20 ml) was stirred at 62° C. for 0.75 h. The mixture was cooled to 25° C. and the catalyst removed filtration through celite. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1) to give the title compound (0.145 g, 68%), δ (250 MHz, CDCl3) 1.48-1.59 (1H, m, CH of CH2), 2.03-2.14 (1H, m, CH of CH2), 2.29-2.41 (2H, m, 2 of CH), 2.63-3.02 (9H, m, 4 of CH2 and CH), 7.14 (1H, dd, J=2.1 and 8.6 Hz, Ar--H), 7.21 (1H, s, Ar--H), 7.49 (1H, d, J=8.6 Hz, Ar--H), 7.60 (1H, d, J=2.1 Hz, Ar--H), 8.54 (2H, s, Ar--H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:36](=[O:38])[CH3:37])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: CC(=O)Cl
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.25 mmol) in dichloromethane (0.6 ml) was added acetyl chloride (0.18 ml, 0.251 mmol) at room temperature. Stirring for 20 h was followed by partitioning between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5 ml-portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (7 mg, 12%) as off-white solid. MS m/e: 440 ([M+H]+)
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]3[N:34]=[N:35][N:36]=[C:26]3[C:25]=2[NH2:37])[CH:12]=1>ClCCCl.C(=O)(O)[O-].[Na+]>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]2[C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]4[N:34]=[N:35][N:36]=[C:26]4[C:25]=3[N:37]=[CH:1]2)[CH:12]=1
Reactant: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: c1cncc(CCCOCCn2cnc3c2c2ccccc2n2nnnc32)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Triethyl orthoformate (21.1 ml, 127 mmol) was added to a solution of N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (30.8 g, 84.7 mmol) in 1,2-dichloroethane (750 ml) and the reaction was heated to reflux for 3 hours. The reaction was cooled to room temperature and diluted with saturated sodium bicarbonate (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (3×75 ml). The combined organic fractions were washed with brine (200 ml), dried (Na2SO4) and concentrated to provide an orange solid. The solid was triturated with diethyl ether and then filtered to yield 28.7 g of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a tan/orange solid.
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH:12]([CH3:13])[S:11][CH2:10][C:8]=2[N:9]=1)C.C(O)(=[O:17])C>Cl>[CH3:13][CH:12]1[C:7]2[C:6](=[O:14])[NH:5][C:4](=[O:17])[NH:9][C:8]=2[CH2:10][S:11]1
Reactant: CCSc1nc2c(c(=O)[nH]1)C(C)SC2
Reactant: CC(=O)O
Agent: Cl
Product: CC1SCc2[nH]c(=O)[nH]c(=O)c21
Yield: 100 %

Procedure:
2-(ethylthio)-5-methylthieno[3,4-d]pyrimidin-4(3H,5H,7H)-one (4.0 g, 17.5 mmol), was suspended in 4.0 mL of conc. HCl and 6.0 mL of glacial acetic acid and the suspension heated at reflux overnight. The mixture was cooled and the precipitated solid collected by filtration, washed with water, and dried to provide 5-methylthieno[3,4-d]pyrimidine-2,4(1H,3H,5H,7H)-dione as a white solid (3.20 g, 100%).
Reaction SMILES: Cl.[CH3:2][CH:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1.C(#N)CC.CCN(C(C)C)C(C)C>>[Cl:11][C:12]1[CH:17]=[C:16]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][C@H:5]2[CH:3]([CH3:4])[CH3:2])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1
Reactant: CC(C)[C@@H]1COCCN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 110 °C
Yield: 44.3 %

Procedure:
(3R)-3-(1-Methylethyl)morpholine hydrochloride salt (3.0 g, 18.11 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (3.22 g, 18.11 mmol, 1 equiv) were charged into a 60 mL sealable tube, followed with addition of propionitrile (25 mL) and Hunig's base (9.49 mL, 54.3 mmol, 3 equiv). The vessel was sealed and heated at 110° C. in an oil bath for 96 hours. The mixture was concentrated in vacuo. The residue was partitioned between cold 2N HCl (100 mL) and EtOAc (2×100 mL). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The acidic aqueous phase was basified with 6N NaOH to pH=10, followed by extraction with EtOAc (2×100 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo to give a dark brownish oil. Both samples were purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3. The combined fractions were concentrated in vacuo. The residue was dried under vacuum at room temperature for 7 hours to give the title compound (2.17 g). LC-MS (ES) m/z=271 [M+H]+.
Reaction SMILES: C([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][CH3:25])[CH:22]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:24]([O:23][C:21]1[CH:22]=[C:17]([N:14]2[CH2:15][CH2:16][C:12]3([NH:8][CH2:9][CH2:10][CH2:11]3)[CH2:13]2)[CH:18]=[N:19][CH:20]=1)[CH3:25]
Reactant: [H][H]
Reactant: CCOc1cncc(N2CCC3(CCCN3Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCOc1cncc(N2CCC3(CCCN3)C2)c1
Yield: 91.1 %

Procedure:
To a solution of 1-benzyl-7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (540 mg, 1.6 mmol) in ethanol (25 mL) in a pressure bottle was added concentrated HCl (1 mL) and Pearlman's catalyst (Pd(OH)2, 20% on carbon, 50 mg). The solution was shaken under 50 psi of hydrogen gas for 8 h. The catalyst was removed by filtration through Celite, and the filter cake was washed with ethanol (20 mL). The solvent was removed by rotary evaporation, and the residue was basified with saturated aqueous sodium bicarbonate to pH 8-9. Solid sodium chloride (2 g) was added, and the mixture was extracted with chloroform (4×20 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford 360.7 mg of the desired compound as a light brown viscous liquid (91.1%).
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[K+]>C(P(CCCCCCCC)CCCCCCCC)CCCCCCC>[C:10]([O:15][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: CO[Si](CCl)(OC)OC
Reactant: C=C(C)C(=O)[O-]
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Agent: [K+]
Product: C=C(C)C(=O)OC[Si](OC)(OC)OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
170.7 g (1 mol) of chloromethyltrimethoxysilane, 11.1 g (0.03 mol) of tri-n-octylphosphine and 0.1 g (0.05 mol % based on silane) of phenothiazine are placed in a reaction vessel at 90° C. and 130.4 g (1.05 mol) of potassium methacrylate are added a little at a time over a period of 1 hour. After stirring at 90° C. for another 1 hour, the reaction is complete. After filtration from the potassium chloride formed, the product is distilled by means of a short-path evaporator, giving 209.3 g (95%) of methacryloxymethyl-trimethoxysilane having a purity of 98.8%.
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=2)[CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3]1.[CH:33]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]O)=[O:34].[O-]CC.[Na+]>C(O)C>[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:38][C:37]3[CH:36]=[C:35]([CH:42]=[CH:41][CH:40]=3)[CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=2)=[CH:3]1
Reactant: O=Cc1cccc(CO)c1
Reactant: c1ccc([P+](Cc2cccc(-c3ccsc3)c2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(C=Cc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
1.21 g of the resulting phosphonium salt was dissolved in 45 ml of ethanol, and 0.35 g of 3-formylbenzyl alcohol and 0.27 g of sodium ethoxide were added. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was distributed between ethyl acetate and water, worked up in a customary manner, and purified by silica gel column chromatography [Wakogel C-300, 100 g; eluting solvent: hexane/ethyl acetate=10/1→5/1] to give 0.34 g (yield 46%) of an E-form of 3-[2-[3-(3-thienyl)-phenyl]ethenyl]benzyl alcohol and 0.34 g of its Z-form.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:6][C:7]([C:9]1[CH:32]=[CH:31][C:12]2[N:13]([CH3:30])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])[CH3:5].[OH-].[Li+]>>[CH3:30][N:13]1[C:12]2[CH:31]=[CH:32][C:9]([C:7]([NH:6][C@@H:4]([CH3:5])[C:3]([OH:33])=[O:2])=[O:8])=[CH:10][C:11]=2[N:15]=[C:14]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: COC(=O)[C@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C)C(=O)O
Yield: 90.1 %

Procedure:
(S)-2-{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (743 mg) was prepared by following General Procedure E starting from (S)-2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (850 mg) and lithium hydroxide (299 mg).