Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23]([OH:25])=O)=[C:21]([NH:26][CH2:27][CH:28]3[CH2:36][CH2:35][C:31]4([CH2:34][CH2:33][CH2:32]4)[CH2:30][CH2:29]3)[N:20]=[C:19]([C:37]#[N:38])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C[CH2:42][N:43]=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:25])[NH:43][CH3:42])=[C:21]([NH:26][CH2:27][CH:28]3[CH2:36][CH2:35][C:31]4([CH2:32][CH2:33][CH2:34]4)[CH2:30][CH2:29]3)[N:20]=[C:19]([C:37]#[N:38])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2C(=O)O)CC1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(NCC2CCC3(CCC3)CC2)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.23 mmol, step 75.4) and 2 M methyl amine solution (0.30 mmol) in DMF (1 mL) are added EDCI-HCl (0.34 mmol) and HoAt (0.34 mmol) at 0° C. The reaction mixture is stirred at room temperature for 1 h. After dilution with AcOEt, the mixture is washed with H2O and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by silicagel column chromatography to give 4-(2-{2-cyano-5-methylcarbamoyl-6-[(spiro[3.5]non-7-ylmethyl)amino]-pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid; 1H-NMR (CDCl3), δ: 0.98-1.07 (2H, m), 1.14-1.85 (2H, m), 1.46 (9H, s), 2.70 (2H, t), 2.93 (3H, d), 3.33 (2H, t), 4.05-4.15 (2H, m), 4.54 (2H, t), 7.80-7.85 (1H, m), 10.10-10.15 (1H, m).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][CH:27]=[CH2:28])[C:22](OC)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:26][CH:27]=[CH2:28])([O:5][CH3:6])=[O:7]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of dimethyl methylphosphonate (15.85 mL, 148 mmol) in THF (99 mL) at −78° C. was added n-butyllithium (93 mL, 148 mmol) slowly. After addition was completed, the reaction mixture was stirred for 30 min and then a solution of (S)-methyl 2-(tert-butoxycarbonylamino)pent-4-enoate (6.8 g, 29.7 mmol) in THF (15 mL) was added slowly. Stirring was continued for another 40 min at −78° C. The reaction was then quenched by adding water and diluted with EtOAc. The organic layer was washed with 1 M HCl, saturated NaHCO3 and brine. The organic layer was then dried over MgSO4, filtered and concentrated to give a clear oil. The crude product was then purified by silica gel chromatography to give the desired product (9.3 g, 98%) as colorless oil. MS (ESI) m/z: 599.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.C1(P(=[CH:33][C:34]#[N:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:33][C:34]#[N:35])=[CH:7][CH:6]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(C=CC#N)cc1

Procedure:
To a stirring solution of 30 in benzene (0.4 M) at room temperature under nitrogen was added (triphenylphosphoranylidene)acetonitrile (1.1 eq). The reaction was refluxed overnight. The benzene was removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed with 1N hydrochloric acid (1×), saturated sodium bicarbonate (1×) and brine (1×) then dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane). (98%) 1H NMR (400 MHz, CDCl3) δ 7.31-7.44 (m, 5H), 5.87 (d, 1H), 3.71 (s, 3H), 3.66 (s, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.C1C=C[NH+]=CC=1.[Br:27][Br-]Br>O>[Br:27][CH2:17][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:19])([F:20])[F:8])[CH:11]=1)=[O:18]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CBr)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
To a toluene solution (423 mL) of commercially available 3′-trifluoromethylacetophenone (79.6 g, 0.423 mol) was added pyridinium bromide perbromide (135.4 g, 0.423 mol) under ice cooling and stirred for 5 hours while heating up to room temperature. The reaction liquid was ice cooled again, followed by dropwise adding 400 mL of distilled water to stop reaction and fractionation. A toluene layer was washed with 400 mL of a saturated aqueous solution of sodium bicarbonate, followed by drying with magnesium sulfate anhydride and concentration under reduced pressure and distillation under reduced pressure to obtain an objective compound (92.35 g, 81.7%).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[C:20]([CH2:30][PH:31]([O:33]C(C)(C)C)=[O:32])([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[O:21][CH2:22][CH3:23])=[O:7])(C)(C)C.C(N(CC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([C:20]([CH2:30][PH:31]([OH:33])=[O:32])([S:24][C:25]3[NH:26][N:27]=[N:28][N:29]=3)[O:21][CH2:22][CH3:23])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:19]
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@](N)(OC)[C@H]2SC1
Reactant: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@](NC(=O)[C@H](O)c3ccccc3)(OC)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.16 g (2 mmol) of 7β-amino-7α-methoxy-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g (2 mmol) of N,N-diethylaniline in 100 ml of dry methylene chloride is stirred at 0°-5° while 0.56 g (2 mmol) of D-O-dichloroacetylmandeloyl chloride in 10 ml of methylene chloride is added dropwise over 10 minutes. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml of cold dilute hydrochloric acid and 50 ml of cold 5% aqueous sodium bicarbonate, dried and evaporated to dryness. The residue is dissolved in a mixture of 10 ml of trifluoroacetic acid and 2 ml of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml of ether and 50 ml of water and adjusted to pH 9.3-9.5 with 5% aqueous sodium carbonate. The organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, layered with ethyl acetate and adjusted to pH 3.0 with dilute hydrochloric acid. After separation of the layers, the aqueous phase is adjusted to pH 7 with sodium bicarbonate and passed through a XAD-7 resin column. The product-containing fractions are combined, stirred with Amberlite IR-120H ion-exchange resin and lyophilized to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:13][C:12]=12.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.ClCCl>CN(C)C=O.O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[N:13][C:12]=12
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccccc1-c1nnn2c1nc(N1CCOCC1)c1ccccc12
Yield: 80.9 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (0.10 g, 0.23 mmol), triethylamine (0.10 ml, 0.7 mmol) and morpholine (0.025 g, 0.25 mmol) in dry N,N-dimethylformamide (2 ml) was stirred at 50° C. under nitrogen for 18 h. The mixture was cooled, then diluted with water (10 ml) and 10% methanol:dichloromethane (5 ml). The two phases were separated by filtration through a PTFE membrane and the organic layer was concentrated. Trituration and washing with ethyl acetate-diethyl ether gave 3-(2-fluorophenyl)-5-(morpholin-4-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.065 g, 81%). δH (360 MHz; DMSO) 3.61 (4H, dd, J=5 and 5), 3.86 (4H, dd, J=5 and 5), 7.34-7.39 (2H, m), 7.42-7.50 (1H, m), 7.77 (1H, dd, J=7 and 7), 8.04-8.10 (2H, m), 8.22 (1H, d, J=8), 8.59 (1H, d, J=8); m/z (ES+) 350 (M+H+).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1>Cl.O.[OH-].[Na+]>[F:18][C:15]([F:16])([F:17])[C:12]1[N:11]=[CH:10][C:9]([C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[N:8]=2)=[CH:14][CH:13]=1
Reactant: COc1nccc(-c2ccc(C(F)(F)F)nc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
A solution of 2-methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine (0.35 g, 1.37 mmol) in concentrated HCl (3.0 mL) was heated under reflux for 16 h. The reaction solution was then cooled to 0° C., diluted with water and basified with aqueous sodium hydroxide. The mixture was then extracted with dichloromethane (2×), a 3:1 mixture of chloroform and 2-propanol (3×), ethyl acetate (4×) and ethyl acetate with 5% methanol (3×). The combined organic extract was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (0.25 g, 75%) as a tan solid: 1H NMR (500 MHz, CD3OD) δ 9.34 (s, 1H), 8.67 (d, J=8.5 Hz, 1H), 8.20 (d, J=6.0 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.08 (d, J=5.5 Hz, 1H).
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[CH2:7][S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9].N1C=CC=C[C:15]=1C[Li]>C1COCC1>[CH2:7]([S@:8]([C:10]([CH3:11])([CH3:12])[CH3:13])=[O:9])[CH:2]([CH3:3])[CH3:15]
Reactant: [Li]Cc1ccccn1
Reactant: CC(C)(C)[S@@](=O)Cc1ccccn1
Solvent: C1CCOC1
Product: CC(C)C[S@@](=O)C(C)(C)C
Temperature: 25 °C

Procedure:
Preparation of (S)-picolinyl t-butylsulfoxide from (S)-tert-Butyl (1R, 2S)-aminoindanol 4-toluene sulfonamide sulfinate: To a picolinyl lithium solution (2 mL, 0.6 M) in THF at −78° C. was added (S)-t-butyl-(1R, 2S)-aminoindanol tosylate sulfinate (130 mg, 0.30 mmol). The mixture was warmed to room temperature and stirred until the starting material was consumed as monitored by TLC. The reaction was quenched by aq. NaHCO3 (20 mL) and diluted with ethyl acetate (20 mL), and the organic phase was washed with water (20 mL) and brine (20 mL). The organic layer was concentrated in vacuo and the residue was purified by chromatography eluted with ethyl acetate to yield 32 mg of the desired product.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:53][CH2:52][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[S:47][C:48]([CH3:51])=[CH:49][CH:50]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:36][CH2:37][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[S:47][C:48]([CH3:51])=[CH:49][CH:50]=4)=[O:45])[CH2:39]3)[CH2:52][CH2:53]2)[S:32][CH:33]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cs4)CC3)C2)s1
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 2 mL) was added to a solution of (9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 27, step c) (0.65 g) in tetrahydrofuran (7 mL). After 1 h, the solution was evaporated in vacuo. Purification by silica gel chromatography, eluting with 20:1 ethyl acetate:triethylamine, gave the subtitled compound as a gum. Yield 0.45 g.
Reaction SMILES: [Cl:1][CH:2]([C:7]1[CH:8]=[C:9]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:23]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[NH4+:49]>CC#N>[Cl:1][CH:2]([C:7]1[CH:8]=[C:9]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[N:23]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:11][CH:12]=1)[C:3]([F:4])([F:5])[F:6].[NH2:49][CH:2]([C:7]1[CH:8]=[C:9]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:23]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: [NH4+]
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [OH-]
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 5 h

Procedure:
4-(5-(1-Chloro-2,2,2-trifluoroethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.177 g, 0.266 mmol) was dissolved in MeCN (6.00 mL) and saturated ammonium hydroxide aqueous solution (0.6 mL, 4.31 mmol) was added at room temperature and the mixture was stirred at the same temperature for 5 h. The reaction mixture was concentrated and the crude product was adsorbed onto silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH (w/NH3 in DCM) to obtain 4-(5-(1-amino-2,2,2-trifluoroethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.165 g, 96%) as a brown foam.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH:30]=3)[C:25]([NH:43][C:44]3[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.11 mL, 0.80 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoic acid (0.3 g, 0.62 mmol) in DCM (10 mL) and stirred for 1 hour. 2-Amino-5-methylpyrazine (135 mg, 1.23 mmol), then pyridine (0.1 mL, 1.23 mmol), were added and the mixture stirred for a further 30 mins before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a colourless oil (82 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]N(C)CCN(C)C.C([Li])(C)(C)C.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2c(cccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran (40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at −78° C. The mixture was stirred at −78° C. for 40 minutes. To the resulting mixture was added iodomethane (5.07 mL) dropwise and the mixture was stirred at −78° C. for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL), washed with brine (40 mL×3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[C:15]([Cl:23])[CH:14]=[CH:13][CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+].CI>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[C:15]([Cl:23])[CH:14]=[CH:13][CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cccc(Cl)c2c1CCN=[N+]=[N-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cccc(Cl)c2c1CCN=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-4-chloro-1H-indol-2-yl]-propanedioic acid dimethyl ester (19.3 mmol) in dry MeOH (0.1 L) at 0° C. under argon was added a 25% NaOMe in MeOH (4.37 mL, 19.11 mmol). The reaction mixture was stirred for 30 min, and MeI (1.82 mL, 29.2 mmol) was added. The mixture was stirred briefly at rt, and then was refluxed overnight. The reaction mixture was concentrated. The residue was taken up with cold H2O. This mixture was extracted with Et2O. The combined Et2O extracts were washed with H2O, dried, filtered, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2), MS (ESI+) 387.0; 1H NMR (300 MHz CDCl3) δ 9.95 (1H), 7.27 (1H), 7.07 (2H), 3.83 (6H), 3.48 (2H), 3.15 (2H), 1.94 (3H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+]>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH3:10])[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: C1COCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCOCC1

Procedure:
BOC-L-Alanine (3.50 mg, 20 mmol) and morpholine (1.74 g, 20 mmol) were coupled according to procedure A (washed with 1N NaOH after acid washes) giving a colorless oil which was used without further purification. Yield 3.94 g, 76%.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:2]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CSc1ccsc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CSc1ccsc1C=O

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][N:13]=[C:12]([C:15](OCC)=[O:16])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(-c2cccc(Cl)c2)on1
Temperature: 50 °C

Procedure:
Sodium borohydride (96.7 g, 2.6 mol) was slowly added to a solution of ethyl 5-(3-chlorophenyl)isoxazole-3-carboxylate (214.5 g, 0.85 mol) in methanol (2.5 L) at 0° C. The reaction mixture was heated at 50° C. for 2 h and was quenched with EtOAc at r.t. Most of the solvent was distilled off and to the remaining crude was added EtOAc. The organic layer was washed with water, saturated brine and concentrated to give the title compound, which was used directly in the next step. MS (M++1)=210.