Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [FH:1].C(Cl)Cl.C[N:6]=[C:7]=[O:8].[CH2:9]([N:11]([CH2:14][CH3:15])[S:12]Cl)[CH3:10]>C(N(CC)CC)C>[CH2:9]([N:11]([CH2:14][CH3:15])[S:12][NH:6][C:7]([F:1])=[O:8])[CH3:10]
Reactant: CCN(CC)SCl
Reactant: CN=C=O
Reactant: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)SNC(=O)F
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Anhydrous hydrogen fluoride (3.0 g, 0.15 mole) was added to 150 ml of methylene chloride at -10° C. Then 8.6 g of methylisocyanate was added, followed by 20.9 g (0.15 mole) of N,N-diethylaminosulfenyl chloride at 0° C. Triethylamine (15.2 g) was then added at 0° C. over a 15-minute period, and the mixture was stirred at +5° C. for 1 hour. The mixture was then extracted with water (100 ml), saturated sodium bicarbonate solution, and water again. After drying (MgSO4), the solvent was removed in vacuo, and the crude residue was vacuum distilled to give 17 g of N-methyl-N-(diethylamino-sulfenyl carbamoyl fluoride, b.p. 57° C./0.8 mm (62.9 percent yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])[N:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:15]([C:11]1[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCCCc1cccc(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cccc(O)n1

Procedure:
To a pressure reaction bottle were added 1.6 g 2-(benzyloxy)-6-butylpyridine, 0.2 g 5% palladium on carbon and 50 ml ethanol. The mixture was hydrogenated at 22 C and 40 psi hydrogen for 16 hours. Following filtration through celite and solvent removal, an oil was obtained that crystallized on standing to give 0.9 g.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[C:12]2=[C:13]([CH2:17][S:18][C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=[CH:9]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOCC.O>[CH2:32]([O:31][C:29]([N:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=[C:19]1[S:18][CH2:17][C:13]1[N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=[CH:9][S:8][C:12]=12)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: c1ccc2[nH]c(SCc3nccc4ccsc34)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)n1c(SCc2nccc3ccsc23)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 44.0 mg (1.10 mmol) of 60% NaH were added 7 ml of dry DMF and 299.2 mg (1.00 mmol) of 2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole. 1/10 H2O (Ia-1). After stirring for 10 min. at room temperature, the solution was added with 130.2 mg (1.20 mmol) of ClCOOEt and stirred for 30 minutes at room temperature. DMF was evaporated under reduced pressure. Water was added to the residue, and the solution was extracted with CH2Cl2. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby 381.0 mg of pale greenish yellow cyrstals were obtained. After being subjected to silica gel column chromatography, the crystals were dispersed with 2 ml of ether, followed by filtration and washed with ether, whereby 335.7 mg (Yield : 90.9%) of the objective compound, 1-ethoxycarbonyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-1) was obtained as crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]O.S(Cl)(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: OCc1nccs1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cc1nccs1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 11 h

Procedure:
To a chloroform (15 ml) solution of thiazole-2-methanol (171 mg, 1.49 mmol) was added thionyl chloride (0.33 ml, 4.47 mmol) and the resulting mixture was stirred at 50° C. for 11 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorobenzenesulfinate (296 mg, 1.49 mmol) and potassium acetate (292 mg, 2.98 mmol). The mixture was stirred at 70° C. for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (169 mg, 41%) was obtained as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([F:11])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]=3[N:26]=2)=[C:4]([F:11])[CH:3]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3F)nc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluorobenzoic acid (5 g) in a mixture of pyridine (50 mL) and DMF (50 mL) at 45° C. was treated with CDI (0.856 g), stirred at 45° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (5.1 g), stirred at ambient temperature for 18 hours and concentrated. The concentrate was dissolved in acetic acid (100 mL), heated at 70° C. for 1 hour and concentrated. The concentrate was partitioned between ethyl acetate and sodium bicarbonate solution and the organic phase was isolated, washed with brine and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[N:16][NH:15][C:14]=12.[H-].[Na+].S(OC)(O[CH3:24])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]2=[N:15][N:16]([CH3:24])[CH:17]=[C:13]2[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccc(-c2nccc3cn[nH]c23)c(Cl)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2ccnc(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 3 h

Procedure:
A mixture of 7-(2,4-dichloro-phenyl)-1H-pyrazolo[3,4-c]pyridine (31; 0.107 g; 0.405 mmol), 4 mL of THF, and 60% sodium hydride/mineral oil (0.020 g, 0.50 mmol sodium hydride) was stirred for 3 h. To the green solution was added dimethyl sulfate (0.040 mL, 0.42 mmol). The resulting yellow, cloudy solution was stirred for 30 m, then quenched with silica gel and concentrated. Column chromatography (0→50% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine as a white solid (32; 0.029 g; 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu](Br)Br>[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(Br)cn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C)CCc1ccc(Oc2cnc(OC(C)C)nc2)cc1
Reaction time: 3 h

Procedure:
5-Bromo-2-isopropoxypyrimidine (100 mg, 0.46 mmol), N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (95 mg, 0.46 mmol), cesium carbonate (180 mg, 0.552 mmol), copper bromide (66 mg, 0.46 mmol) were stirred in 5 ml of NMP at 160° C. under argon for 5 h. Following addition of equimolar amounts of the components stirring was continued at 160° C. for a further 3 h. The batch was filtered, the filtrate was concentrated and admixed with ethyl acetate and water, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 3 mg (1%), M+H+: 344.23.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (1.0 g, 3.25 mmol) and (RS)-[3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K24) (1.31 g, 3.25 mmol) according to the general procedure M. Obtained as a light yellow foam (970 mg, 47%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:17])[C:9]([F:19])([F:18])[CH2:8][N:7]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[CH:20]1([N:7]2[CH2:8][C:9]([F:19])([F:18])[C:10](=[O:17])[N:11]([CH2:12][C:13]([F:14])([F:15])[F:16])[C:5]3[CH:4]=[N:3][C:2]([NH:26][C:27]4[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[O:32])=[CH:29][C:28]=4[O:43][CH3:44])=[N:25][C:6]2=3)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1N(CC(F)(F)F)c2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2CC(F)(F)F
Yield: 47.2 %

Procedure:
A mixture of 0.10 g (0.26 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-150), 0.072 g (0.27 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.074 g (0.39 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-70:30) gave 0.075 g of 4-[9-cyclopentyl-7,7-difluoro-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-150) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: NC(=O)c1c(N)sc2ccccc12
Temperature: 40 °C

Procedure:
To obtain a final product with a 3H-pyrimido[4,5-b]benzo[d]thiophen-4-one heterotricyclic core moiety, the 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (or derivative thereof) intermediate is mixed with an oxidizing agent such as of 2,3-dicyano-5,6-dichloro-parabenzoquinone (DDQ) in a non-polar solvent such as toluene at room temperature. The reaction is mixed for a few hours at moderate heat (e.g. 40° C.). The solvent is then removed under reduced pressure, and the residue is filtered and then optionally purified by column chromatography (e.g., on a silica gel with elution by a 8:2 mixture of dichloromethane and ethylacetate) to yield 2-aminobenzo[b]thiophene-3-carboxamide (or derivative thereof). This intermediate is then reacted according to the general procedure described above, in place of the 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide intermediate (see Scheme 3(b)).
Reaction SMILES: [Cl:1][C:2](CCl)=[CH2:3].[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:7].[CH2:15](Cl)CCl>[Zn].C(O)(=O)C>[Cl:1][C:2]([CH2:7][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH3:15])=[CH2:3]
Reactant: CC(=O)c1ccccc1
Reactant: ClCCCl
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: CC(=O)O
Product: C=C(Cl)CC(C)(O)c1ccccc1

Procedure:
33.26 of 2,3-dichloro-1-propene were added dropwise to a mixture of 20.00 g of acetophenone, 40 g of ethylene dichloride, 60 g of 5% acetic acid and 19.52 g of zinc powder at 50° C., and the resultant mixture was allowed to react at the same temperature for 10 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase was washed with 7% sodium carbonate aqueous solution and dried over magnesium sulfate. The desiccant was filtered off, and the ethylene dichloride was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 22.24 g of 2-chloro-4-phenyl-1-penten-4-ol; nD25 =1.536, FI-MS m/e 178(M-H2O+), 180 (M-H2O+2+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:36])=O>COC(C)(C)C>[Cl:36][C:15]1[N:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(-c2cc3ncccc3cn2)cc(OC)c1OC
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Product: COc1cc(-c2cc3ncccc3c(Cl)n2)cc(OC)c1OC

Procedure:
565 mg 7-(3,4,5-Trimethoxy-phenyl)-[1,6]-naphthyridine (5.2) and 15 μL N,N-diethylaniline were stirred into 4 mL phosphorus oxychloride overnight at 100° C. and at ambient temperature over 2 days. The reaction mixture was evaporated down, and a small amount of ethyl acetate was added. Upon scratching a precipitate were formed. Methyl-tert-butylether was added and the precipitate was isolated and dried overnight at 50° C. under vacuo.
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.[P:10]([OH:13])([OH:12])[OH:11].Cl.C=O>>[P:10]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:13])([OH:12])=[O:11]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: Cl
Product: CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Reaction time: 19 h
Yield: 99 %

Procedure:
N-acetyl sarcosine (XX) (20.0 g, 152.5 mmole), phosphorous acid (12.59, 152.4 mmole), and concentrated HCl (37.6 g) were mixed and refluxed in a 120° C. oil bath. Formalin, 37% (13.6 g, 167.6 mmole) was added dropwise over 20 min. and the reaction was continued for an additional 19 h. HPLC analysis indicated a-99% yield of N-methylglyphosate (XXI) based on moles of (XX) charged.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11])[C:3]1=[O:13].[BH4-].[Na+].CC(C)=O.[BH4-]>CCO>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11])[CH:3]1[OH:13]
Reactant: Cc1ccc(C)c2c1CC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc(C)c2c1CC(C)C2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
8.95 g of 2,4,7-trimethylindanone (51.4 mmol) were dissolved in 70 ml of EtOH; the solution was cooled to 0° C. and 2.00 g of NaBH4 (51.8 mmol) were added to it in small aliquots. At the end of the addition, the reaction mixture was allowed to reach ambient temperature and then heated at 50° C. for 3 hours and 30 min. The reaction mixture was cooled to 0° C., and 50 ml of acetone were slowly (careful: exothermic reaction!) added to it to deactivate the residual borohydride. All volatiles were then removed in vacuo, the white solid obtained was treated with 50 ml of 1H2O and stirred for 30 min. The organic layer was extracted with Et2O (2×100 ml), washed with H2O, dried and essiccated in vacuo to leave 9.06 g of a white solid (100%).
Reaction SMILES: [BH4-].[Li+].[CH3:3][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:5]1[C:16](OCC)=[O:17].CO>C1COCC1>[OH:17][CH2:16][C@@H:5]1[C@@H:4]([CH3:3])[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CCOC(=O)[C@@H]1[C@@H](C)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium borohydride (6.6 mmol, 3.31 mL of a 2M in THF solution) was added dropwise to an ice cold THF solution of 1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate (850 mg, 3.3 mmol) and methanol (0.133 mL, 3.3 mmol). The reaction was warmed to room temperature and then stirred for 4 hours. The reaction was quenched with i-propanol then with saturated NaHCO3. The reaction mixture was extracted 3× with ethyl acetate. The organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound, which was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (t, J=7.0 Hz, 3 H) 1.3 (m, 9 H) 1.9 (m, 1 H) 2.2 (m, 1 H) 3.1 (m, 2 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 4.7 (m, 1 H).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[NH:6][CH:5]=[C:4]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.Cl.O>C(O)(=O)C.O1CCOCC1.[Pd]>[ClH:1].[ClH:1].[NH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3](=[O:2])[C:4]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:5][NH:6]2)=[N:13][CH:12]=1
Reactant: N#Cc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reaction time: 96 h

Procedure:
10.0 g (38.0 mmol) of the compound from Example 12 are initially charged in 300 ml of acetic acid. 20 ml of a 4 N solution of hydrogen chloride in dioxane and 5.0 g (4.7 mmol) of palladium on carbon (10%) are added and the mixture is hydrogenated at RT under atmospheric pressure for 96 h. Water is then added until the organic solid formed has gone back into solution, and the catalyst is filtered off through silica gel. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate mixture). The product obtained is then stirred in a 4 N solution of hydrogen chloride in dioxane for 30 min, and the solid is filtered off and dried under high vacuum. The solid is then dissolved in about 300 ml of water, and the solution is lyophilized.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][CH:13]([CH3:36])[CH:14]([NH:19][C:20]([C:22]1[S:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)=[CH:25][N:26]=1)=[O:21])[C:15]([O:17][CH3:18])=[O:16]>>[CH:1]1([CH2:7][CH2:8][C:9]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:24]3[S:23][C:22]([C:20]([NH:19][CH:14]([CH:13]([CH3:36])[CH3:12])[C:15]([O:17][CH3:18])=[O:16])=[O:21])=[N:26][CH:25]=3)=[CH:28][CH:29]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)CCC3CCCCC3)cc2)s1)C(C)C
Yield: 49 %

Procedure:
The title compound was synthesized analogous to Example 27, using 3-cyclohexylpropanoyl chloride and intermediate 2. Yield: 49%; 1H NMR (DMSO-d6, 300 MHz): δ 10.09 (s, 1H), 8.74 (d, 1H), 8.35 (s, 1H), 7.71 (s, 4H), 4.32 (t, 1H), 3.69 (s, 3H), 2.36 (t, 2H), 2.30 (m, 1H), 1.73 (m, 5H), 1.51 (q, 2H), 1.17 (m, 4H), 0.96 (t, 6H), 0.92 (m, 2H); MS (ESI) m/z 472.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][CH:22]=[CH2:23])[C:10]=2[CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[CH2:21]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][NH:8][CH2:9][C:10]1=2)[CH:22]=[CH2:23].[F:32][C:33]([F:38])([F:37])[C:34]([O-:36])=[O:35]
Reactant: C=CCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C=CCn1c2c(c3ccccc31)CCNC2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dichloromethane solution (20 ml) of 2-t-butoxycarbonyl-9-allyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (624 mg, 2.0 mmol) was mixed with anisole (2 ml) and trifluoroacetic acid (3 ml) and stirred at room temperature for 6 hours. By removing the solvent by evaporation under a reduced pressure, 9-allyl-2,3,4,9-tetrahydro-pyrido[3,4-b]indole was obtained as trifluoroacetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C@H:8]([C:44]1[C:52]2[S:51][C:50](=[O:53])[NH:49][C:48]=2[C:47]([OH:54])=[CH:46][CH:45]=1)[CH2:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:43][CH2:42][C:30]2([O:35][CH2:34][CH2:33][N:32](C(=O)C(F)(F)F)[CH2:31]2)[CH2:29][CH2:28]1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>O.CO>[O:35]1[C:30]2([CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:10]([CH2:9][C@H:8]([OH:7])[C:44]3[C:52]4[S:51][C:50](=[O:53])[NH:49][C:48]=4[C:47]([OH:54])=[CH:46][CH:45]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:43][CH2:42]2)[CH2:31][NH:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC2(CC1)CNCCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of potassium carbonate (165 mg) in water (24 mL) was added to a solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(9-(4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)nonyl)carbamate (example 183-222, step c) (495 mg) in MeOH (24 mL). The resulting mixture was stirred at RT for 4 h. Methanol was removed by evaporation under a stream of nitrogen keeping the reaction mixture at 30° C. Water (20 mL) and brine (80 mL) were added and the mixture was extracted with EtOAc (5×60 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The brown solid residue was purified by silica gel chromatography eluting with 0-20% (2M NH3 in MeOH)/DCM to give the subtitled compound as a yellow solid. Yield 323 mg.