Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[C:4]2[C:30]([CH3:36])([C:31]([O:33]CC)=O)[C:29](=[O:37])[NH:28][C:5]=2[N:6]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[N:10]=2)[N:8]=1>>[NH2:2][C:3]1[C:4]2[C:30]([CH3:36])([C:31]([NH2:1])=[O:33])[C:29](=[O:37])[NH:28][C:5]=2[N:6]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:24])([F:23])[F:25])[N:10]=2)[N:8]=1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Reactant: N
Product: CC1(C(N)=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 50 °C

Procedure:
Ammonia (2.0M in MeOH, 11 mL, 22 mmol) was added to ethyl 4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 157, (150 mg, 0.289 mmol, single enantiomer from SFC separation on Chiralpak AD column). The resultant mixture was heated at 50° C. for 16 hours. The reaction solution was then concentrated in vacuo, and the residue purified by preparative TLC using 5% MeOH in DCM (with 0.5% NH4OH) as the eluent to give the indicated compound. 1H NMR (500 MHz, DMSO-d6): δ 8.66 (d, J=8.7 Hz, 1H); 8.02 (d, J=1.4 Hz, 1H); 7.45 (br s, 1H); 7.27 (dd, J=8.7, 1.7 Hz, 1H); 7.19 (br s, 1H); 6.79 (br s, 2H); 4.82 (t, J=6.8 Hz, 2H); 2.95-2.85 (m, 2H); 1.56 (s, 3H). m/z=504.1 (M+H).
Reaction SMILES: CC1C=CC(S([CH2:11][N:12]=[CH2:13])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1CCCC1.[H-].[Na+]>O>[C:17]1([C:16]2[C:15]([C:14]([O:24][CH3:25])=[O:23])=[CH:11][NH:12][CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C

Procedure:
p-Tosylmethyl isocyanide (1 g., 5 mmoles) and methyl cinnamate (0.8 g., 5 mmoles) were combined in 50 ml. of tetrahydrofuran and dissolved by stirring at room temperature. The solution was cooled to -50° C. and sodium hydride (57% dispersion in oil, 210 mg., 5 mmoles) added. After stirring for 15 minutes at -50° C., the reaction was warmed to room temperature and stirred for approximately 16 hours. Water (20 ml.) was added and the product extracted into 35 ml. ether. The ether was back-washed with 20 ml. of water, evaporated to dryness, the residue triturated with ether and methyl 4-phenylpyrrole-3-carboxylate (230 mg., m.p. 182°-185° C., m/e 201) recovered by filtration. The product was recrystallized from acetone/hexane (210 mg., m.p. 184°-187° C.).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:53]1[CH2:58][CH2:57][O:56][CH2:55][CH:54]1[C:59]1[C:67]2[S:66][C:65]([NH2:68])=[N:64][C:63]=2[C:62]([O:69][CH3:70])=[CH:61][CH:60]=1>C1COCC1.C(Cl)(Cl)Cl>[O:53]1[CH2:58][CH2:57][O:56][CH2:55][CH:54]1[C:59]1[C:67]2[S:66][C:65]([NH:68][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][N:19]=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[CH:12]=3)=[N:64][C:63]=2[C:62]([O:69][CH3:70])=[CH:61][CH:60]=1
Reactant: O=C(O)c1ccnc(COCCN2CCCC2=O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COCCN4CCCC4=O)c3)nc12

Procedure:
From 2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxymethyl]-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+84.1° (c=1.02, CHCl3), ES-MS m/e (%): 513 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.[CH2:23]([N:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:26](Cl)=[O:27])[CH3:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[N:25]([CH2:23][CH3:24])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: CCN(C(=O)Cl)c1ccccc1OC
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C#CC(C)(C)N1CCC(OC(=O)N(CC)c2ccccc2OC)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-ethyl-N-(2-methoxyphenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-[N-ethyl-N-(2-methoxyphenyl)-carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]3[NH:25][N:24]=[N:23][N:21]=3)[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(Oc2c(C)nn(CC#N)c2C)c2c1CCC2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)nn(Cc3nnn[nH]3)c2C)c2c1CCC2
Temperature: 95 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a stirred solution of [4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile (3.0 gm, 0.0101 mole) in Dimethylformamide (30 ml), Sodium azide (1.2 gm, 0.0185 mole) and Triethylamine hydrochloride (4.0 gm, 0.0303 mole) were added at room temperature (27-30° C.). The reaction mixture was stirred at 90-100° C. for 4 hours. The reaction mixture was cooled and poured into dilute Hydrochloric acid (100 ml) and stirred for 30 minutes. The separated solid was filtered and dissolved in Ethyl acetate (100 ml). The Ethyl acetate layer was dried over Sodium sulphate and distilled under vacuum to get a 1.5 gm of desired product as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[S:30])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[BrH:1].[O:15]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[S:30][CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=3[CH3:10])[N:31]=2)=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cc1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc(Oc4ccccc4)cc3)n2)c(C)s1
Yield: 90.2 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (200 mg, 0.64 mmol) was allowed to react with 4-phenoxyphenylthiourea (158 mg) as described in Example 154, step (a) to give 300 mg (88% yield) of methyl 4-(2-{[4-(phenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C22H18N2O3S3, 454.6 (M+H), found 455.2.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:21]4[CH:22]=[N:23][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:25][CH:26]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([C:21]3[CH:22]=[N:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)[C:14]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AH) (1.00 g, 0.0022 mol) was triturated in acetone (20 mL) and 5N hydrochloric acid solution was added dropwise. The mixture was stirred at ambient temperature for 20 hours and neutralized with saturated sodium bicarbonate solution. The precipitate was collected by filtration, washed with water twice and dried to give 4-[4-amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclo-hexanone as an off-white solid (purity 94% (HPLC), 0.90 g, 0.0022 mol) ):
Reaction SMILES: [CH3:1][Mg]Cl.[CH:4]1[C:13]2C(=[CH:9][CH:10]=[CH:11][CH:12]=2)C=C(C#N)[N:5]=1.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[C:18]([C:17]1[N:5]=[CH:4][C:13]2[C:20]([CH:16]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:19])[CH3:1]
Reactant: C1CCOC1
Reactant: N#Cc1cc2ccccc2cn1
Reactant: C[Mg]Cl
Product: CC(=O)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
Methyl magnesium chloride (2.6 ml of a 3.0M solution in THF) was added dropwise to a solution of isoquinoline-3-carbonitrile at 0°-5° C. After the addition the reaction mixture was stirred at room temperature for 1 hour, then quenched with water. Hydrochloric acid (2M aqueous solution) was added to the reaction mixture until the aqueous phase was pH2. After stirring for 30 minutes the aqueous was neutralised with sodium bicarbonate (solid) and extracted with ether (×2). The combined extracts were washed with water, dried and concentrated to give a crystalline solid. Recrystalisation from hexane gave 3-acetyl-isoquinoline (0.55 g, 14% yield) as a pale yellow solid m.p. 84.4°-86.8° C. 1H NMR: 2.83(3H,s); 7.69-7.81(2H,m); 7.99(1H,m); 8.04(1H,m); 8.49(1H,m); 9.29(1H,s) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:2]2[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: NC1CCN(Cc2cc(F)cc(C(F)(F)F)c2)CC1
Reactant: N#Cc1ccc(Cl)nn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 6-chloro-pyridazine-3-carbonitrile (D4) (1.39 g, 9.95 mmol), 1-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-ylamine (D7) (2.5 g, 9.04 mmol) and diisopropylethylamine (2.63 ml, 14.92 mmol) in acetonitrile (2 ml) was stirred at 120° C. for 30 min, under microwave irradiation ((Biotage MW-oven). The mixture was then diluted with dichloromethane (50 ml) and extracted with a saturated solution of sodium carbonate. The organic layer was separated, dried (Na2SO4), filtered, evaporated in vacuo and the residue purified by column chromatography (silica gel; 0-2.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The residue precipitated from diisopropylether to yield E17 (2.76 g, 73%) as a solid. C18H17F4N5 requires 379. Found 380 (MH+); mp: 151.4° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](=O)[CH2:16][Br:17]>C(C(C)=O)C>[BrH:17].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]1[N:1]=[C:2]2[N:6]([CH:16]=1)[C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[S:3]2
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCC(C)=O
Product: Br
Product: COc1ccccc1-c1cn2c(n1)sc1ccccc12
Yield: 19 %

Procedure:
To 70 ml of methyl ethyl ketone were added 7 g of 2-aminobenzothiazole and 10 g of o-methoxyphenacyl bromide and the mixture was refluxed for 10 hours. The reaction mixture was filtered while it was hot to recover crystals precipitated. The crystals were washed with methyl ethyl ketone, and dried to provide 3.0 g of 2-(o-methoxyphenyl)imidazo[2,1-b]-benzothiazole hydrobromide having a melting point of 263°-265° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[OH-].[Na+].C(O)(=[O:19])C>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([OH:19])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: Fc1cc2c(Cl)nc(Cl)nc2cc1Cl
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc2cc(Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 334 mg (1.33 mmol) 2,4,7-Trichloro-6-fluoro-quinazoline (WO9532205) and 6.6 mL 1N NaOH aq. in 2 mL THF was stirred for 2 h at room temperature. The pH of the mixture was adjusted to pH=4-5 with acetic acid. The precipitate was filtered of to yield the title compound which was used in the consecutive step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[O:21]([CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[O:21]([CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 88.3 %

Procedure:
To a cold solution of 2,3-dioxo-2,3-dihydro-1-H-indole-5-sulfonylchloride (3.80 g, 15.5 mmol ) in a 1:1 mixture of THF:CHCl3 (194 mL) was added drop-wise via syringe pump a solution of (2S)-2-(phenoxymethyl)pyrrolidine (2.85 g, 16.1 mmol, 1.03 eq) (J. Med. Chem, 44, 2014, 2001) and N,N-diisopropylethylamine (5.61 mL, 32.2 mmol, 2 eq) in CHCl3 (30 mL) over a period of 50 minutes under a dry N2 atmosphere with cooling in an ice bath. After stirring at room temperature for 64 hr the reaction mixture was concentrated and the crude product was flash chromatographed twice using Biotage KP silica gel, and gradient of 98/2 CH2Cl2/CH3OH as eluent on the first column and 90/10 CH2Cl2/CH3OH as eluent on the second column to give the title compound as a dark green solid (5.29 g, 88% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 385 [M−H]. MS: (ES+) m/z 387 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:32]([C:34]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([CH3:45])=[C:39]2[C:35]=1[CH:36]=[CH:37][N:38]2[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:33]>C1COCC1.[Li+].CC([N-]C(C)C)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[C:8]([CH:32]([OH:33])[C:34]3[C:42]([O:43][CH3:44])=[CH:41][C:40]([CH3:45])=[C:39]4[C:35]=3[CH:36]=[CH:37][N:38]4[C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[S:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2ncsc2c1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2ccc(C#N)cc2s1
Reaction time: 0.33 h

Procedure:
To a solution of 6-cyanobenzothiazol (CAS #:58249-61-9) (54.60 mg, 0.341 mmol) in THF (1.06 mL), LDA in Heptane/THF/Ethylbenzene (205 uL, 0.409 mmol) was added at −78° C. After 20 mins, a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (79 mg, 0.273 mmol) in THF (1.68 mL) was added to the reaction mixture at −78° C. After stirring for 1.5 h, the reaction was quenched with MeOH, sat. aq. NH4Cl solution and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified using FCC eluting with Heptane/EtOAc to provide the title compound. MS (ESI−) m/z 448 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:9]([NH:17]C(=O)[C@@H](O)C3C=CC=CC=3)[CH2:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)C.CCOC(C)=O.[OH-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:9]([NH2:17])[CH2:8]2)=[CH:28][CH:29]=1
Reactant: O=C(N[C@H]1Cc2ccccc2N(Cc2ccc(F)cc2)C1)[C@@H](O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: N[C@H]1Cc2ccccc2N(Cc2ccc(F)cc2)C1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of (S)—N—((S)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylacetamide (350 mg, 0.90 mmol) in absolute ethanol (20 mL) was added concentrated sulfuric acid (2 mL). The reaction mixture was stirred at 85° C. for 24 hours. The mixture was diluted with EtOAc (100 mL), 6 M NaOH aqueous solution (20 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (100 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography using a gradient (0-10% MeOH in EtOAc). The desired product (S)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-amine was obtained as yellow oil (169 mg, 73% yield). 1H NMR (DMSO-d6) 400 MHz δ 7.32-7.25 (m, 2H), 7.18-7.10 (m, 2H), 6.91-6.85 (m, 2H), 6.50-6.42 (m, 2H), 4.49 (d, J=16.8 Hz, 1H for AB system), 4.42 (d, J=16.8 Hz, 1H for AB system), 3.36-3.28 (m, 2H), 3.18-3.10 (m, 1H), 3.01 (dd, J=11.0, 8.6 Hz, 1H), 2.84 (dd, J=15.7, 2.7 Hz, 1H), 1.70 (br. s, 2H). LCMS m/e 258 (M+H).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=1)[C:5](N[C@@H](C1C=CC=CC=1)CO)=[O:6])[CH3:2].C(=O)([O-])[OH:42].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=1)[C:5]([OH:6])=[O:42])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)N[C@H](CO)c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 90 °C
Yield: 54 %

Procedure:
(2S)-2-Ethoxy-N-[(1S)-2-hydroxy-1-phenylethyl]-3-{4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl}propanamide (0.45 g, 0.84 mmol) was dissolved in a mixture of 1M sulphuric acid (17 ml) and dioxane/water (1:1.39 ml) and heated to 90° C. for 88 h. The pH of the mixture was adjusted to 3 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 ml) and the organic phase was washed with water (50 ml), brine (25 ml), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in petroleum ether to afford the title compound (0.19 g, 54%) as a white solid. mp: 89-90° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([CH2:7][CH:8]([NH:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])[C:9](=[O:26])[NH:10][CH:11]([C:14]([C:16]1[O:20][N:19]=[C:18](C2SC=CC=2)[N:17]=1)=[O:15])[CH2:12][CH3:13])(=[O:6])=[O:5].C1C=CC2N(O)N=NC=2C=1.N[C@@H](CC)C(C1ON=[C:53]([C:56](C)([CH3:58])[CH3:57])N=1)O>ClCCl>[C:56]([C:18]1[N:17]=[C:16]([CH:14]([OH:15])[CH:11]([NH:10][C:9]([CH:8]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])[CH2:7][S:4]([CH2:3][CH:2]([CH3:36])[CH3:1])(=[O:5])=[O:6])=[O:26])[CH2:12][CH3:13])[O:20][N:19]=1)([CH3:58])([CH3:57])[CH3:53]
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(-c2cccs2)no1
Reactant: CC[C@H](N)C(O)c1nc(C(C)(C)C)no1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(O)c1nc(C(C)(C)C)no1
Reaction time: 0.33 h
Yield: 104.7 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methylpolystyrene (0.526 g, 1 mmol, loading 1.9 mmol/g) was suspended in dichloromethane (20 mL). 3-(2-methyl-propane-1-sulfonyl)-2-[(morpholine-4-carbonyl)-amino]-propionic acid (0.242 g, 0.6 mmol, reference Example 5) and HOBt (0.114 g, 0.85 mmol) were added and the reaction mixture was stirred for 20 minutes. (2S)-2-Amino-1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (0.107 g, 0.5 mmol, Reference Example 6) was added and stirring continued for 5 hours. Silicycle Triamine (1.27 g, 5 mmol) was added and the mixture stirred for 15 hours. The reaction mixture was filtered under suction and the filtrate concentrated to give morpholine-4-carboxylic acid [1-{1-[(3-tert-butyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide (0.271 g), [LC/MS m/z=518(M+H+)].
Reaction SMILES: [CH:1](C1C=CC(CC2C(=O)NC3C=CC(Cl)=CC=3C(C3C=CC(O)=CC=3)=N2)=CC=1)([CH3:3])[CH3:2].C([C:34]1[CH:61]=[CH:60][C:37]([CH2:38][CH:39]2[C:45](=[O:46])[N:44]([CH3:47])[C:43]3[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:42]=3[C:41]([C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][CH:54]=3)=[N:40]2)=[CH:36][CH:35]=1)(C)C>>[CH:1]([C:35]1[CH:36]=[C:37]([CH:60]=[CH:61][CH:34]=1)[CH2:38][CH:39]1[C:45](=[O:46])[N:44]([CH3:47])[C:43]2[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:42]=2[C:41]([C:53]2[CH:54]=[CH:55][C:56]([OH:59])=[CH:57][CH:58]=2)=[N:40]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3NC2=O)cc1
Reactant: CC(C)c1ccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3N(C)C2=O)cc1
Product: CC(C)c1cccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3N(C)C2=O)c1

Procedure:
1H NMR (300 MHz, DMSO-d6) δ 1.18 and 1.21 (two d, 6H), 2.84 (heptet, 1H), 3.3-3.4 (m, 5H; contains NMe singlet at 3.34), 3.82 (t, 1H), 6.85 (d, 2H), 7.0-7.3 (m, 5H), 7.38 (d, 2H), 7.64 (d, 1H), 7.77 (dd, 1H), 9-11 (br s, 1H). MS, m/z 433.2 [M+1]. (Z)-3-(4-Isopropylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. 1H NMR (300 MHz, DMSO-d6) 1.15 (d, 6H), 2.82 (septet, 1H), 3.24-3.38 (m, 2H), 3.63 (m, 1H), 6.79 (m, 2H), 7.10-7.30 (m, 8H), 7.59 (dd, 1H), 9.45 (s, 1H), 10.61 (s, 1H). MS, m/z 419.3 [M+1]. (Z)-3-(4-Isopropylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one. 1HNMR (300 MHz, DMSO-d6) δ 1.15 (d, 6H), 2.84 (septet, 1H), 3.26-3.41 (m, 5H), 3.77 (m, 1H), 6.84 (m, 2H), 7.10-7.40 (m, 7H), 7.63 (d, 1H), 7.73 (dd, 1H), 10.2 (br s, 1H). MS, m/z 433.3 [M+1]. Method B: