Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([C:22](OC)=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.B>O1CCCC1>[CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([CH2:22][OH:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COC(=O)c1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
To the mixture of methyl 2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-carboxylate (30 mg, 0.087 mmol) in tetrahydrofuran (2 mL) was added a tetrahydrofuran solution of borane (1.5 mL, 1.5 mmol) at 0° C. After being stirred at 70° C. for 4 hours, the mixture was quenched with methanol (5 mL) at 0° C. The solvent was removed in vacuo to give a residue which was purified by flash column (ethyl acetate/hexane, 3:7) to afford 16 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 305. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (d, J=8.0 Hz, 1 H), 7.56-7.44 (m, 3 H), 7.25 (s, 1 H), 7.16-7.07 (m, 4 H), 5.44 (t, J=4.2 Hz, 1 H), 4.86 (s, 2 H), 4.85 (s, 2 H), 4.18 (brs, 2 H), 3.04 (brs, 2 H), 1.80 (brs, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]1[CH3:21].[BH4-].[Na+]>C(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]2[CH3:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1cn(CCCN)c(C)n1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cn(CCCNC(C)c2ccc(Cl)cc2)c(C)n1
Product: Cl

Procedure:
In a similar manner to Example 1, a mixture of 4'-chloroacetophenone (4.0 g) and 1-(3-aminopropyl)-2,4-dimethylimidazole (4.0 g) was heated at 115°-120° C. for 7 hours then reduced with sodium borohydride (2.0 g) in ethanol (70 ml) over 18 hours. The solid obtained was triturated with propan-2-ol and filtered to give N-[1-(4-chlorophenyl)ethyl]-3-(2,4-dimethylimidazol-1-yl)propylamine dihydrochloride, m.p. 218°-220° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=1[O:23][CH3:24].C([Li])CCC.CN(C)[CH:32]=[O:33].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:20]([C:18]1[CH:17]=[CH:16][C:15]([O:23][CH3:24])=[C:14]([C:3]2[C:2]([CH:32]=[O:33])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[C:5]([O:12][CH3:13])[CH:4]=2)[CH:19]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1C=O
Reaction time: 1 h

Procedure:
2-Bromo-5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl (1.29 g) is dissolved in dry tetrahydrofuran (30 ml) and thereto is added dropwise 1.6M n-butyllithium in hexane at −78° C., and the mixture is stirred for 1 hour and thereto is added N,N-dimethylformamide (1.2 ml), and the mixture is stirred for 1.5 hours. To the reaction solution are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:3) to give 5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (733 mg). MS (m/z): 353 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[Cl:13].[Br:14]Br>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([Br:14])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: Nc1c(Cl)c(C(=O)O)nc(Cl)c1Br
Temperature: 70 °C
Yield: 91 %

Procedure:
To a solution of methyl 4-amino-3,6-dichloropyridine-2-carboxylate (18 g, 81 mmol) in 100 mL fuming sulfuric acid was added bromine (15 mL, excess). The resulting mixture was heated to 70° C. for 30 min, then allowed to cool to room temperature. This material was poured into ice water (1000 mL) and extracted with EtOAc (4×500 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to yield a brown solid. The crude product was purified via reverse phase HPLC (50% acetonitrile/water) to give 21 g of 4-amino-3,6-dichloro-5-bromopyridine-2-carboxylic acid as a white solid (91% yield); mp 201-202° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[SH:13].[Cl:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27](=[O:30])[CH2:28][CH3:29])[CH:24]=2)[CH2:19]1>>[ClH:14].[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[S:13][CH2:15][CH2:16][CH2:17][N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27](=[O:30])[CH2:28][CH3:29])[CH:24]=2)[CH2:19]1
Reactant: CCC(=O)c1ccc2c(c1)CN(CCCCl)C2
Reactant: Cn1c(S)nnc1-c1ccccc1
Product: CCC(=O)c1ccc2c(c1)CN(CCCSc1nnc(-c3ccccc3)n1C)C2
Product: Cl

Procedure:
The title compound was prepared in analogy to method 1.5 from 4-methyl-5-phenyl-4H-1,2,4-triazole-3-thiol (1.43 mmol, 0.33 g) and 1-[2-(3-chloropropyl)-2,3-dihydro-1H-isoindol-5-yl]propan-1-one (1.43 mmol, 0.36 g; preparation in analogy to 1.4 from isoindoline as disclosed in WO 0125200). Yield: 0.24 g.
Reaction SMILES: COC1C=NNC=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12].[Cl:19][C:20]1[C:21]([CH2:25][O:26][CH3:27])=[N:22][NH:23][CH:24]=1.[CH3:28]OC1C=NNC=1>>[Cl:19][C:20]1[C:21]([CH2:25][O:26][CH3:27])=[N:22][NH:23][C:24]=1[C:16]1[C:17]([CH3:18])=[CH:8][C:9]([CH3:28])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COc1cn[nH]c1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]ncc2OC)c1
Reactant: COCc1n[nH]cc1Cl
Product: COCc1n[nH]c(-c2cc(C(=O)OC)c(C)cc2C)c1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 244.6, except 4-chloro-3-(methoxymethyl)-1H-pyrazole (compound 281.2) was used instead of 4-methoxy-1H-pyrazole (compound 244.4).
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH2:15]>O>[NH:15]1[C:1]2=[C:3]3[N:8]([CH2:7][CH2:6][NH:5]2)[CH2:9][CH2:10][CH2:11][N:12]3[CH2:13][CH2:14]1
Reactant: NCCNCCCNCCN
Reactant: O=CC=O
Solvent: O
Product: C1CN2CCNC3=C2N(C1)CCN3
Temperature: 25 °C
Reaction time: 10 h

Procedure:
9.04 g (62.4 mmol) of a 40% by weight aqueous glyoxal solution are slowly added dropwise to a solution of 10.00 g (62.4 mmol) of N,N′-bis(2-aminoethyl)-1,3-pro-panediamine in 30 ml of water at 0° C. The mixture is maintained at this temperature for 1 hour and then stirred at ambient temperature for 10 hours. After evaporation of the water, compound 12 is isolated quantitatively in the form of a pale yellow solid and is used for the following stage without subsequent purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(Cl)cccc2-n2cnc(CO)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 81.2 g (234.8 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in 450 ml of dry tetrahydrofuran is heated to about 50° and a suspension of 6.1 g (279 mmol) of lithium borohydride in 60 ml of tetrahydrofuran is added dropwise to the solution obtained. The suspension is subsequently heated to boiling under reflux for 3 hour. The mixture is cooled to room temperature and there are added dropwise thereto firstly 40 ml of 3N hydrochloric acid and then 260 ml of a solution consisting of 130 ml of conc. hydrochloric acid and 130 ml of water. The solution obtained is stirred at 40° for 15 minutes, the tetrahydrofuran is distilled off in vacuo and the aqueous residue is made alkaline with 25 percent ammonia. The precipitated material is then filtered off under suction, washed with water and dried at 80° in high vacuum. There is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(hydroxymethy)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 303°-305° .
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:14][C:15]2[N:20](C(OC(C)(C)C)=O)[N:19]=[C:18]([NH:28][C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:16]=2[N:17]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Cl.[Cl-].[Na+]>C(O)C.O1CCOCC1>[CH3:3][C:2]([NH:10][C:11]([C:13]1[S:14][C:15]2[NH:20][N:19]=[C:18]([NH:28][C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:16]=2[N:17]=1)=[O:12])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(NC(=O)c1nc2c(NC(=O)c3ccc(N4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
0.19 g (0.32 mmol) of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-(4-morpholin-4-ylbenzoylamino)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 7 ml of ethanol is placed in a 50 ml round-bottomed flask. 1.6 ml (6.4 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the reaction mixture is stirred for 15 hours at 25° C. A further 1.6 ml (6.4 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 40 ml of dichloromethane and 40 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (40° C.). The yellow residue is purified by flash chromatography (msilica=30 g; eluent: 97/3 dichloromethane/methanol). 0.097 g of N-(1-methyl-1-phenylethyl)-3-(4-morpholin-4-ylbenzoylamino)-1H-pyrazolo[4,3-d]thiazole-5-carboxamide is thus obtained in the form of a yellow foam. m.p.K=266° C. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (s, 6H); 3.29 (masked m, 4H); 3.75 (m, 4H); 7.04 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.31 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 7.99 (d, J=8.5 Hz, 2H); 8.50 (broad s, 1H); 10.8 (broad m, 1H); 13.6 (broad m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:29]2[S:28][N:27]=[CH:26][C:25]=2[CH:24]=[CH:23][C:22]=1[C:30]([OH:32])=[O:31]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[C:29]3[S:28][N:27]=[CH:26][C:25]=3[CH:24]=[CH:23][C:22]=2[C:30]([OH:32])=[O:31])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)c1ccc2cnsc2c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (1.05 g, 5.55 mmol) in anhydrous THF (20 mL) at −78° C. was added a 1.0 M solution of LHMDS in hexanes (8.3 mL, 8.3 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (547 mg, 2.78 mmol) in anhydrous THF (20 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 min, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous HCl (ca. 50 mL) and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, MeOH in DCM) to give the title compound as a brown solid (584 mg, 58%). LCMS (method B): RT=3.76 min, [M−H]−=365/367.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[C@@:21]([C:25]1[S:29][C:28]([SH:30])=[N:27][CH:26]=1)(O)[CH2:22][CH3:23].C([O-])([O-])=[O:34].[K+].[K+]>CN1C(=O)CCC1>[OH:34][CH2:23][CH2:22][C@H:21]([C:25]1[S:29][C:28]([S:30][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][C:8](=[O:12])[O:9]3)=[CH:4][CH:3]=2)=[N:27][CH:26]=1)[C:20]([F:32])([F:31])[F:19]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@](O)(c1cnc(S)s1)C(F)(F)F
Reactant: O=c1cc(-c2cccnc2)c2ccc(F)cc2o1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2cccnc2)c2ccc(Sc3ncc([C@@H](CCO)C(F)(F)F)s3)cc2o1
Temperature: 120 °C

Procedure:
A mixture of 7-fluoro-4-pyridin-3-yl-2H-chromen-2-one (0.177 g, 0.73 mmol), (2S)-1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol (0.214 g, 0.88 mmol) and K2CO3 (0.203 g, 1.47 mmol) in NMP was heated at 120° C. overnight. The mixture was cooled to rt and partitioned between aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 95:5 to 80:20) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.81 (dd, 1H), 8.72 (dd, 1H), 7.82 (dt, 1H), 7.78 (s, 1H), 7.51-7.59 (m, 2H), 7.33-7.40 (m, 2H), 6.42 (s, 1H), 2.74 (br s, 1H), 2.12 (q, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]4[CH2:58][CH2:57][CH2:56][CH2:55][N:54]4[CH:59]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]4[CH2:58][CH2:57][CH2:56][CH2:55][N:54]4[CH:59]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 213 from 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium hydroxide solution in ethanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][CH3:14])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]([NH:13][CH3:14])[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(C#N)COCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CNC(CN)COCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
A solution of 3-benzyloxy-2-methylamino-propionitrile (5.0 g) in toluene (90 mL) was cooled to −78° C. and DIBAL-H solution (90 mL of a 20% in toluene) was added drop wise under nitrogen atmosphere. Reaction mixture was slowly warmed to room temperature and then left at stirring for 17 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with 10 mL methanol and then 50 mL water. The volatiles where evaporated in vacuo and the crude material was taken up in 50 mL water and acidified to pH=1 with 1M HCl. The aqueous phase was extracted with ethyl acetate and the aqueous layer was subsequently basified to pH=14 with 30% NaOH solution. The free diamine was extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated to afford the desired 3-(benzyloxy)-N2-methylpropane-1,2-diamine (3.8 g) as a brown oil, which was used in the next reaction without further purification. MS (ES+): 195.1 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>O>[C:3]([CH:2]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(C)CBr
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)C(C)=O
Temperature: 60 °C

Procedure:
To a solution of 100 g (0.77 mol) of ethyl acetoacetate in 500 ml of DMF 30.7 g (0.77 mol) of 60% suspension of NaH in mineral oil was added in small portions by vigorous stirring at 60° C. This mixture was additionally stirred for 1 h, and then 105.5 g (0.77 mol) of isobutylbromide was added. The resulting mixture was stirred for 3 h at 90° C., then cooled to room temperature, and 1500 ml of cold water was added. The product was extracted by 3×300 ml of dichloromethane. The combined organic extract was evaporated at reduced pressure using rotary evaporator. Fractional rectification of the residue gave the title product, b.p. 75-80° C./4 mm Hg. Yield 80.5 g (56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=O.[N:13]1([C:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:19])[CH:17]=[CH:16]N=C1.[BH4-].[Na+].Cl.O1CCC[CH2:29]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[CH2:5][O:7][C:17]1[CH:16]=[C:21]2[N:22]([CH3:29])[CH2:23][CH2:24][N:20]2[C:18](=[O:19])[N:13]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN1CCn2c1cc(OCc1cc(F)c(F)c(Cl)c1)nc2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-4,5-difluorobenzoic acid (0.75 g, 3.9 mmol) and di(1H-imidazol-1-yl)methanone (CDI) (0.695 g, 4.28 mmol) in tetrahydrofuran (THF) (10 mL) was stirred under nitrogen at room temperature for 1 h, and then a solution of NaBH4 (0.221 g, 5.84 mmol) in water (2.0 mL) was added dropwise. The reaction mixture was stirred at 10° C. for 16 h, and adjusted to pH=1 with 1 N HCl solution, concentrated to remove solvent and extracted with ethyl acetate. Separated organic part was washed with a solution of NaHCO3 and concentrated. Purification via preparative TLC afforded the title product (0.41 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:50])=[C:4]([S:29]([N:32](CC2C=CC(OC)=CC=2OC)[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15]1[C:16]([N+:26]([O-])=O)=[N:17][N:18](C2CCCCO2)[CH:19]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:26][C:16]1[C:15]([C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][C:7]2[CH:6]=[CH:5][C:4]([S:29]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)(=[O:31])=[O:30])=[C:3]([F:50])[C:2]=2[Cl:1])=[CH:19][NH:18][N:17]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])c(Cl)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1Cl
Yield: 10 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (198 mg, 0.341 mmol) prepared in Example 91a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (16 mg, 9.4%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:32]C)[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:32])[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCN1CCOCC1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C1c2c(c3n(c(=O)c2O)CCCCN(CCN2CCOCC2)C3=O)CCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (30 mg, 0.06 mmol) and 33% hydrogen bromide in acetic acid (0.4 mL) in dioxane (2 mL) was stirred at room temperature for 30 minutes. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: Cl.COC1C=CC(C[N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[O:21])=[CH:10]2)=CC=1>O1CCOCC1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([C:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][CH:10]=2)=[O:21])=[N:23][CH:24]=1
Reactant: COc1ccc(Cn2cc(C(=O)c3ccc(C)cn3)c(=O)c3ccccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1
Temperature: 120 °C
Yield: 26.1 %

Procedure:
A 4M solution of hydrochloric acid in dioxane (4 mL) was added to 381 mg (0.991 mmol) of 1-(4-Methoxy-benzyl)-3-(5-methyl-pyridine-2-carbonyl)-1H-quinolin-4-one and was heated in a pressure tube at 120° C. for 18 h. The reaction was concentrated and saturated sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane (3×20 mL). The crude product was purified by flash column chromatography using a gradient of 70:30 ethyl acetate/methanol to afford 68.4 mg of 3-(5-Methyl-pyridine-2-carbonyl)-1H-quinolin-4-one.
Reaction SMILES: [Br:1][C:2]1(C)[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]1[CH3:9].CN([CH:14]=[O:15])C.[CH2:16]([Li])CCC>C(OCC)C.CCCCCC>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([CH:14]=[O:15])=[CH:6][C:7]=1[CH3:16]
Reactant: [Li]CCCC
Reactant: CN(C)C=O
Reactant: CC1C=C(Br)C=CC1(C)Br
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(C=O)cc(C)c1Br
Reaction time: 0.67 h

Procedure:
A solution of 2,5-dibromoxylene (8.0 g, 30.3 mmol) in diethyl ether (120 mL) is cooled to −78° C. and then treated with n-buthyllithium (20 mL, 1.6 M in hexane). After stirring for 40 min, DMF (6 mL) is slowly added. The mixture is warmed to it and stirred for 1 h. The mixture is cooled again to −78° C. before another portion of n-butyllithium (5 mL) is added. The reaction mixture is allowed to warm to it and stirred for another hour. The reaction is quenched by adding 5% aq. HCl. The mixture is extracted with EA, and the extract is concentrated in vacuo. The crude product is purified by CC on silica gel eluting with heptane:EA 5:1 to give 4-bromo-3,5-dimethyl-benzaldehyde (8.2 g) as a white soft solid.