Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(N(CC)CC)C.Cl>ClCCl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][S:2]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(CN)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNS(=O)(=O)NC(=O)OC(C)(C)C)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
A solution of chlorosulfonylisocyanate (11.32 g, 80 mmol) in dichloromethane (120 mL) was cooled to 0° C. Tert-butyl alcohol (7.65 mL, 80.0 mmol, 1.0 equiv.) was added via addition funnel. The mixture was stirred at 0° C. for 1.5 h. To this mixture, a solution of aminoacetaldehyde dimethyl acetal (8.76 mL, 80.0 mmol, 1.0 equiv.) and triethylamine (TEA, 33.4 mL, 240 mmol, 3.0 equiv.) in methylene chloride (DCM 120.0 mL) was added drop-wise via addition funnel. The reaction was warmed to room temperature and stirred overnight. The reaction was treated with 0.1 N hydrochloric acid and the organic layer was washed with brine, dried over sodium sulfate and concentrated to give the desired product (15.6 g, 68.5%) as a crude off-white solid, which was used for the subsequent reaction without further purification: 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.62 (t, 1H, J=6.0 Hz), 4.38 (t, 1H, J=5.5 Hz), 3.24 (s, 6H), 2.96 (dd, 2H, J=5.8 Hz), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:4][CH:3]=1.O.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(Cl)cc3)C3CCCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(CC2(C(=O)O)CC2)c1)C(c1ccc(Cl)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.60 g (14.1 mmol) of (+/−)-tert-butyl 1-(3-{[(4-chlorophenyl)(cyclopentyl)acetyl]amino}-benzyl)cyclopropanecarboxylate were dissolved in 41.8 ml of dichloromethane and, after addition of a drop of water, 10.9 ml of TFA were added at RT. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was initially dried under high vacuum and then triturated with diisopropyl ether. The resulting solid was filtered off with suction and dried under high vacuum. This gave 4.52 g (77.8% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[C:22]1(B(O)O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cccc4ccccc34)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), naphthalene-1-boronic acid (99 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in mixture of 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(naphthalen-1-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (DMSO, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (d, 1H), 7.79 (d, 1H), 7.3-7.5 (m, 5H), 7.1 (s, 1H), 6.9 (d, 1H), 4.21 (m, 2H), 3.4 (m, 2H), 2.77-3.0 (m, 9H), 2.3 (m, 5H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1(CC2C3C(=CC(OC)=CC=3)CCN2)CCCC1.[Cl:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46](O)=[O:47])[CH:41]=[CH:42][C:43]=1[Cl:44].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)(=O)C>[ClH:37].[N:1]1([CH2:6][C:7]2([C:46](=[O:47])[CH2:45][C:40]3[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cccc2c1C(CN1CCCC1)NCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1ccc2c(c1)CCNC2CN1CCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1C(CN1CCCC1)(C(=O)Cc1ccc(Cl)c(Cl)c1)NCC2
Product: Cl

Procedure:
Prepared as Ex. No. 1, from 4.3 g (17.48 mmoles) of a mixture containing 1-(pyrrolidin-1-yl)methyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline and 1-(pyrrolidin-1-yl)methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline, 4.3 g (20.98 mmoles) of 3,4-dichlorophenylacetic acid, and 8.0 g (38.80 mmoles) of dicyclohexylcarbodiimide, in 110 ml of dry methylene chloride. The silica gel chromatographic column was eluted with CH2Cl2, containing increasing amounts of MeOH (0.6-2.5%); 1.5 g of the crude product were obtained and dissolved in 40 ml of ethyl acetate. The solution was brought to acidic pH with HCl/diethyl ehter and the precipitate filtered, washed and dried, to yield 1.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C(OC1C=C(C(C2C(Cl)=NC=CN=2)[NH:49]C(=O)C(C)(C)C)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:49])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 55 °C

Procedure:
1-(3-Benzyloxyphenyl)-3-tert-butyl-8-chloroimidazo[1,5-a]pyrazine: A mixture of POCl3 (3 mL, 5 g, 33 mmol) and N-[(3-benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2,2-dimethylpropionamide (109 mg, 0.266 mmol) is heated to 55° C. for 6 d. POCl3 is evaporated, a cold solution of NH3 in iPrOH (2 M, 5 mL) is added, the suspension is filtered, and the solid is washed with iPrOH. The crude material contained in the combined filtrate and washings is adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with hexanes:EtOAc 10:1 (1-22)→5:1 (23-40)], yielding the title compound as yellow oil that slowly solidifies; 1H NMR (CDCl3, 400 MHz) δ 1.59 (s, 9H), 5.13 (s, 2H), 7.03 (d, J=8.0 Hz, 1H), 7.27-7.42 (m, 7H), 7.46 (d, J=7.2 Hz, 2H), 7.87 (d, J=4.8 Hz, 1H). MS (ES+): m/z 392.1/394.0 (12/4) [MH+].
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14]CCC)[C:10](=[O:18])[C:9]([C:19]([OH:21])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:18])[C:9]([C:19]([Cl:24])=[O:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(=O)c(C(=O)Cl)nn(-c2ccccc2)c1=O
Yield: 88 %

Procedure:
Intermediate g (3.0 g, 0.01 mol) was added to thionyl chloride (10 V/W, 30 mL). The mixture was warmed up under stirring to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (3 g) in a yield of 88%,
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7]C)=O.[CH:16](N(C(C)C)CC)(C)[CH3:17].ClC(OCC1C=CC=CC=1)=O>C1COCC1>[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:4][C:5]1([OH:7])[CH2:17][CH2:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C[C@H](N)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: N[C@@H](CC1(O)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
(S)-Methyl 3-amino-3-(4-fluorophenyl)propionate hydrochloride (4.5 g) was dissolved in THF (30 ml) and cooled to 0° C. After the addition of diisopropylethylamine (8.8 g), benzyl chloroformate (4.3 g) was slowly added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated by rotary evaporation, dichloromethane (50 ml) was added and the mixture was washed twice with NH4Cl solution. Subsequently, the organic phase was dried with MgSO4, filtered and concentrated. The residue (5.72 g) was taken up in THF, titanium tetraisopropoxide (0.49 g) was added, and ethylmagnesium bromide (3 N, 17.9 ml) was added dropwise over the course of 1 hour. After 24 hours, the reaction solution was poured into cold 2 N sulfuric acid (150 ml) and extracted three times with dichloromethane. The combined organic phases were dried with MgSO4, filtered and concentrated. The residue was purified by preparative HPLC. The resulting (S)-1-(4-fluorophenyl)-2-(1-hydroxycyclopropyl)ethyl]carbamic acid benzyl ester (0.76 g) was dissolved in methanol (20 ml), 5% Pd/C was added and hydrogenation was effected under hydrogen pressure 2 bar. After filtration and concentration, the product (87 mg) was thus obtained with a molecular weight of 329.3 g/mol (C19H20FNO3), MS (ESI): m/e=330 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:33]=[CH:32][C:23]4[C:24]([C:28]([O:30]C)=[O:29])=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.O.[OH-].[Li+]>C1COCC1.CO.CO>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:33]=[CH:32][C:23]4[C:24]([C:28]([OH:30])=[O:29])=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Yield: 78.3 %

Procedure:
To a stirred solution of methyl 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylate 89d (540 mg, 1.16 mmole) in THF/MeOH/MeOH (6 ml, 1:1:1) was added lithium hydroxide monohydrate (54 mg, 1.29 mmole). When the ester disappeared by thin layer chromatography (tic), the organic solvents removed under reduced pressure, and the aqueous residue was neutralized with 2N HCl. The white solid which precipitated was collected by filtration and dried under vacuum to give the desired acid (411 mg, 83%). 1H NMR (DMSO-d6) δ 13.02 (1H, bs), 8.57 (1H,d, J=5.3 Hz), 8.05 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.68 (1H, s), 7.25 (1H, d, J=8.5 Hz), 6.75 (1H, d, J=5.5 Hz), 4.10–3.85 (3H, m), 3.65–3.45 (2H, m), 3.25 (3H, d, J=9.4 Hz), 2.74 (3H, s), 2.15–1.95 (2H,m).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)=[C:6]3[C:12](/[CH:13]=[CH:14]/[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[N:11][N:10](CC4C=CC(OC)=CC=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:51]>>[ClH:51].[CH:1]1([C:4]2[C:5]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:6]3[C:12](/[CH:13]=[CH:14]/[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: COc1ccc(Cn2nc(/C=C/c3cccnc3)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: C(=C/c1n[nH]c2ncc(C3CC3)c(N3CCNCC3)c12)\c1cccnc1
Product: Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of (E)-tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-(2-(pyridin-3-yl)vinyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (385 mg, 0.68 mmol) in 25% TFA/CH2Cl2 was stirred at room temperature. Then the mixture was concentrated in vacuo, and the residue was evaporated from toluene (3×10 mL). TFA (10 mL) was added to the residue, and the mixture was stirred at 60° C. for 4 hours. The solvent was then removed in vacuo, and the residue was evaporated from toluene (20 mL). The residue was dissolved in CH2Cl2 (2 mL) and 2M HCl in Et2O was added. The mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and washed with additional Et2O and dried to provide (E)-5-cyclopropyl-4-(piperazin-1-yl)-3-(2-(pyridin-3-yl)vinyl)-1H-pyrazolo[3,4-b]pyridine hydrochloride salt (210 mg, 74% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 9.76 (br s, 2H), 9.24 (s, 1H), 9.00 (d, 1H), 8.80 (d, 1H), 8.30 (s, 1H), 8.07 (dd, 1H), 7.93 (d, 1H), 7.59 (d, 1H), 3.78-3.72 (m, 4H), 3.33-3.26 (m, 4H), 2.17-2.10 (m, 1H), 1.06-1.02 (m, 2H), 0.83-0.79 (m, 2H); LCMS (APCI+) m/z 347.1 (M+H)+, Retention time=2.09 minutes.
Reaction SMILES: Br[C:2]1(Br)[CH2:10][CH2:9][C:8]2[NH:7][N:6]=[C:5]([CH3:11])[C:4]=2[C:3]1=O.BrC1CCC2NN=C(C)C=2C1=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH2:35])=[S:34]>CCO>[CH3:11][C:5]1[C:4]2[C:3]3[N:35]=[C:33]([NH:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[S:34][C:2]=3[CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: Cc1n[nH]c2c1C(=O)C(Br)(Br)CC2
Agent: Cc1n[nH]c2c1C(=O)C(Br)CC2
Solvent: CCO
Product: Cc1n[nH]c2c1-c1nc(Nc3ccccn3)sc1CC2

Procedure:
According to Scheme 4 Step 5: A solution of a mixture of 5,5-dibromo-3-methyl-6,7-dihydro-1H-indazol-4(5H)one, 5-bromo-3-methyl-6,7-dihydro-1H-indazol-4(5H)-one (37.5:62.5, 173 mg) and of 1-(pyridin-2-yl)thiourea (0.67 mmol, 102 mg) in EtOH (2.4 mL) was stirred under reflux for 3 hours. The precipitate formed was filtered, was washed with a saturated solution of NaHCO3, water, EtOH and Et2O and was dried to yield 8-methyl-N-(pyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (46 μmol, 13 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[CH2:28]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[S:32])[CH3:29]>C(Cl)Cl>[CH2:34]([NH:33][C:31]([S:32][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[N:30][CH2:28][CH3:29])[CH3:35]
Reactant: CCNC(=S)NCC
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN=C(NCC)SCC(=O)NC1C(=O)N2C(c3nnn[nH]3)C(C)(C)S[C@H]12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52 g (0.039 mole) of N,N'-diethylthiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a white solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2-[N,N'-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: FC1C=[C:4](C=CC=1)[CH:5]=[O:6].[N+]([CH:13]([OH:15])[CH3:14])([O-])=O.C(OC(=O)C)(=O)C.[F:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:37])[CH:31]([N+:34]([O-:36])=[O:35])[CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=1.C(Cl)(=O)C>C(N(CC)CC)C>[F:23][C:24]1[CH:25]=[C:26]([CH:30]([O:37][C:5](=[O:6])[CH3:4])[CH:31]([N+:34]([O-:36])=[O:35])[CH2:32][O:33][C:13](=[O:15])[CH3:14])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(O)[N+](=O)[O-]
Reactant: O=Cc1cccc(F)c1
Reactant: O=[N+]([O-])C(CO)C(O)c1cccc(F)c1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(C(OC(C)=O)c1cccc(F)c1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
0.5 ml of triethylamine catalyst are added to a mixture of 6.0 g (0.05 moles) of 3-fluorobenzaldehyde and 4.5 g (0.05 moles) of nitroethanol. The mixture is stirred for one hour and then allowed to stand at 0° C. for 72 hours. 15 g (0.15 moles) of acetic anhydride are added under stirring to the resulting crude 1-(3-fluorophenyl)-2-nitro-1,3-propanediol, and then 2 ml of acetyl chloride are added dropwise to the mixture. The mixture is stirred at 50° C. for 2 hours and then poured onto 100 g of ice under stirring. The resulting oily product starts to crystallize within about 15 minutes. The crude product is separated from the water, dissolved in 50 ml of chloroform, the solution is washed acid-free with ice-cold water, decolourized with activated carbon, filtered, and the solvent is evaporated under reduced pressure. 10.8 g (72%) of the title compound are obtained; m.p.: 94° C.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:15]([C:17]1[CH:28]=[CH:27][C:20]2[N:21]([CH3:26])[C:22]([CH2:24][NH2:25])=[N:23][C:19]=2[CH:18]=1)=[O:16].C(N(C(C)C)C(C)C)C.Cl[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][N:47]=1.Cl>O>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:15]([C:17]1[CH:28]=[CH:27][C:20]2[N:21]([CH3:26])[C:22]([CH2:24][NH:25][C:46]3[N:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=3)=[N:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Temperature: 100 °C

Procedure:
1.5 g (3.25 mmol) of 1-methyl-2-aminomethylbenzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide trifluoroacetate were stirred into 10 mL of N-ethyldiisopropylamine and heated to 100° C. for 15 minutes. After the addition of 720 mg (5.25 mmol) of 2-chloro-5-cyanopyridine, the reaction mixture was heated to 125° C. for 2 hours. After cooling to ambient temperature and stirring with about 20 mL of water, the pH was adjusted to 4 by the addition of 1N hydrochloric acid and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with saline solution and dried over sodium sulfate. After evaporation of the solvent, the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down. Yield: 1.05 g (67% of theory), C26H25N7O (483.6); mass spectrum: (M+H)+=484.
Reaction SMILES: [C:1]([N:8]1[CH2:13]CC(=O)C(Br)C1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[O:18][C:19]([C:21]([NH2:23])=S)=[O:20].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O-])(=O)=O)=[CH:27]C=1.C1C=C[NH+]=CC=1>C1(C)C=CC=CC=1.O>[C:1]([N:8]1[C:29]2[CH2:30][CH2:25][NH:23][CH2:27][C:28]=2[S:31][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:24][CH2:21][C:19]([O-:18])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: CCOC(=O)C(N)=S
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CSC2=C1CCNC2
Product: CCC(=O)[O-]
Yield: 317 %

Procedure:
N-boc-3-bromo-4-piperidone (110 gm, 0.395 mole) obtained in step IV was dissolved in 500 ml of dry toluene. Ethyl thioxamate (68.4 g, 0.514 mole) obtained in step II and PPTS (10 gm, 0.039 mole) were added to toluene solution. Mixture was refluxed azeotropically for 8 h, followed by concentration. The residue obtained was taken in water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulphate and concentrated. Residue obtained was purified by column chromatography using 1% MeOH/CH2Cl2 as eluent to get the 39.0 gm of N-boc-4,5,6,7-tetrahydrothiazolo-[5,4-c]-pyridine-2-ethylcarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23]CC(C(O)=O)C)[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[C:5]2=[CH:4][CH:3]=1.Cl.CNC.CCN=C=N[CH2:49][CH2:50][CH2:51]N(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:75][N:76]([CH:78]=[O:79])[CH3:77]>>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:50]([C:78](=[O:79])[N:76]([CH3:77])[CH3:75])([CH3:51])[CH3:49])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.174 mmol), dimethylamine hydrochloride (28 mg, 0.348 mmol), EDC.HCl (66 mg, 0.348 mmol), HOBt (47 mg, 0.348 mmol) and DIPEA (135 mg, 1.044 mmol) in anhydrous DMF (3 mL) was stirred at room temperature overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (50 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:8]1[CH:7]=[C:6]2[C:10]([CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[N:9]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2cc([N+](=O)[O-])ccc2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-Nitroindazole (1.00 g, 6.13 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was added. The mixture was stirred for 30 minutes and then (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.32 g 9.16 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 2.18 (s, 6H), 2.81 (t, 2H, J=6.44), 4.60 (t, 2H, J=6.44), 7.78 (m, 1H), 8.00 (m, 1H), 8.82 (s, 1H), 8.89 (m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.