Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:13]([O:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:14].C(N(CC)CC)C.O>C1COCC1>[CH2:13]([O:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=2)=[CH:24][CH:25]=1)[CH3:14]
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A solution of 3-dimethylaminobenzoyl chloride (0.19 g, 1.01 mmol) in THF (6 ml) was added dropwise to a solution of 4-(4-aminophenyl)butyric acid ethyl ester (0.26 g, 1.24 mmol) and triethylamine (0.31 g, 3.11 mmol) in THF (8 ml) under ice cooling. The reaction solution was stirred at room temperature for 8 hours, then added with water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous ammonium chloride and saturated brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1) to obtain 4-[4-(3-dimethylamino-benzoylamino)-phenyl]-butyric acid ethyl ester as a brown oily substance (0.36 g, yield: 97.5%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:24][C:25]1[N:30]=[CH:29][C:28](I)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:10]=[C:11]([C:12]#[N:13])[C:6]3=[N:5][CH:4]=2)=[CH:27][N:26]=1
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: Nc1ncc(I)cn1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cnc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 2-amino-5-iodopyrimidine (107 mg, 0.5 mmol) according to general procedure II. Obtained as a dark brown solid (5 mg, 2%). MS (ISP) 405.3 [(M+H)+]; mp 290° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[CH:43][CH:44]=[CH:45][C:36]=5[Cl:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc2c1CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(Cl)cccc5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (245 mg, 0.517 mmol), 5-chloro-1,2,3,4-tetrahydroisoquinoline (175 mg, 1.03 mmol), cupric acetate (94.8 mg, 0.517 mmol), pyridine (84 μL, 1.0 mmol), 4 Å molecular sieves (139 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 3 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.88-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.04 (t, J=6.0 Hz, 2H), 3.36 (t, J=6.0 Hz, 2H), 4.16 (s, 2H), 4.22-4.36 (m, 3H), 7.02 (d, J=7.6 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.62 (s, 1H), 7.66 (s, 1H), 7.69 (s, 1H). MS(ES+): m/z=508.77/511.16 (52/20) [MH+]. HPLC: tR=3.00 min (ZQ2, polar—5 min).
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:6][CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>>[CH3:21][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:5]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[C:2]2[N:1]=[C:42]([C:41]3[CH:40]=[CH:39][C:38]([C:37]([F:36])([F:47])[F:48])=[CH:46][CH:45]=3)[O:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:22])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)/C(N)=N/O)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2noc(-c3ccc(C(F)(F)F)cc3)n2)cc1)C(=O)O

Procedure:
Similarly prepared by condensation of tert-butyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate with 4-trifluoromethylbenzoyl chloride, followed by standard TFA hydrolysis.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:19]([O-])=O)=[C:14]([CH:18]=2)[C:15]([NH2:17])=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:19][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1N
Temperature: 25 °C
Yield: 66 %

Procedure:
5-Benzenesulfonyl-2-nitro-benzamide (3.13 g, 10.23 mmol) was suspended in absolute ethanol (200 mL), treated with 10% Pd/C (1.5 g) and then with ammonium formate (9.7 g, 153 mmol). The mixture was stirred at reflux. After a couple of hours the reaction was complete. After cooling to room temperature the reaction was filtered over celite and the panel was washed with EtOH. Evaporation of the filtrate left the crude product that was taken up with a small amount of methanol and added dropwise to 400 mL of iced water kept under stirring. The solid thus formed was filtered and washed with water affording 1.87 g of title compound (66% yield).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(CO)CO
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: OCC(CO)Nc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C
Yield: 38 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 336 mg (5 equivalents) of 2-amino-1,3-propanediol, and the mixture is then heated at 120° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride-methanol: 50-50. Partial drying and drying under vacuum at 50° C. are carried out. 91.4 mg of expected product are obtained.
Reaction SMILES: [CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([O:23]C)=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:26]#[N:27])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1>C(O)(=O)C>[CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([OH:23])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:26]#[N:27])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COC[C@H](C1CC1)n1cc(C#N)nc(Nc2cc(C)c(OC)nc2C)c1=O
Solvent: CC(=O)O
Product: COC[C@H](C1CC1)n1cc(C#N)nc(Nc2cc(C)c(O)nc2C)c1=O
Reaction time: 1 h

Procedure:
(S)-4-(1-Cyclopropyl-2-methoxyethyl)-6-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (3.00 g, 8.12 mmol) and KI (6.2 g, 37.3 mmol) in glacial acetic acid (80 mL) was heated at 100° C. with stirring for 1 h. LC-MS analysis indicated>98% conversion to the required product. The reaction mixture was cooled to ambient temperature and acetic acid was evaporated in vacuo. The residue was partitioned between ethyl acetate (3×150 mL) and H2O (˜100 mL). The organic layer was washed with brine (100 mL) and then dried over Na2SO4. The organic layer was evaporated in vacuo and the dark brown residue was purified by Biotage SiO2 column chromatography (5% MeOH/CH2Cl2, Rf=0.16) to give pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-hydroxy-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.33 g, 81%) as pale yellow solid: 1H NMR (CDCl3) δ 7.85-7.55 (br. s, 1H), 7.48 (s, 1H), 4.16-4.12 (m, 1H), 3.73 (dd, 1H, JAB=10.3 Hz, JAX=4.9 Hz), 3.66 (dd, JBX=2.2 Hz), 3.35 (s, 3H), 2.40-2.20 (br s, 6H), 1.39-1.32 (m, 1H), 0.85-0.79 (m, 1H), 0.67-0.61 (m, 1H), 0.55-0.51 (m, 1H), 0.34-0.29 (m, 1H); LRMS (ESI) m/e 356 [(M+H)+, calcd for C18H21N5O3 356]; tR=1.8 min (Solvent A: MeOH:H2O:TFA=10:90:0.1; Solvent B: MeOH:H2O:TFA=90:10:0.1; 0% B in A to 100% B in A linear gradient in a 3 min run with 1 min hold time at the end, λ=280 nm).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][CH2:14][CH3:15].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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>[C:16]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH2:13][CH2:14][CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1oc(=O)c2ccccc2c1I
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 16.3 %

Procedure:
4-Iodo-3-propyl-1H-isochromen-1-one (intermediate C20.2, 0.80 g, 2.55 mmol), phenylboronic acid (0.39 g, 3.18 mmol), Pd(PPh3)4 (0.15 g, 0.127 mmol) and Cs2CO3 (1.16 g, 3.57 mmol) were reacted in DMF (10 ml) at 80° C. for 3 hrs. The reaction was the partitioned between AcOEt and 1 M HClaqueous, washed with 1 M HClaqueous brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified on a silica 500 Biotage cartridge eluting with a gradient of Hexane and AcOEt to give the title compound (0.11 g, 15.9%) as a yellowish oil.
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].CO>O>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([NH2:22])[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (2.2 g) prepared as described in Example 1, ammonium acetate (7 g), sodium cyanoborohydride (0.4 g) and methanol (28 ml) was stirred at room temperature for four days. The reaction mixture was poured into a mixture of ice and water and the resulting mixture extracted with ether. The ether extract was washed with water, dried and the ether removed to leave 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as an oil which was identified by standard analytical techniques as the compound of Example 1 in the form of its free base.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:12])[C:10]=2[N:11]=1.B([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])(O)O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[NH2:12][C:9]1[C:10]2[N:11]=[C:2]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Nc1ncnc2ccc(Cl)nc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Temperature: 80 °C

Procedure:
6-chloropyrido[3,2-d]pyrimidin-4-amine 3-A (500 mg, 2.8 mmol) in acetonitrile (5 mL) was treated with 3-borono-benzoic acid (CAS 269404-73-6) (560 mg, 3 mL), PDCL2(DPPF) (202 mg, 0.28 mmol) and 1 M POTASSIUM CARBONATE solution (8 mL). The reaction vial was purged with nitrogen, and heated to 80° C. for 1 hour. LCMS showed 100% conversion to desired product. Yellow ppt. was filtered and LCMS indicated it is pure product 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)benzoic acid 14. The filtrate was concentrate and purified with reverse phase C-18 column to provide more product. LC/MS (ESI+): m/z 267 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:46])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]3[S:45][CH:44]=[CH:43][C:35]=3[N:36]=[C:37](S(C)(=O)=O)[N:38]=2)=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C(=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:46])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]3[S:45][CH:44]=[CH:43][C:35]=3[N:36]=[C:37]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[N:38]=2)=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2nc(S(C)(=O)=O)nc3ccsc23)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2nc(NCCCN3CCCCC3)nc3ccsc23)cc1
Temperature: 75 °C
Yield: 26.1 %

Procedure:
A solution of 3-aminopropylpiperidine (60 μl, 0.38 mmol) and N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyrimidin-4-yl]benzamide (Method 54, 81 mg, 0.15 mmol) in N,N-dimethylacetamide was heated first to 50° C. for 23 hours and then further heated to 75° C. for a period of 16 hours. The reaction mixture was evaporated to dryness and the crude residue purified by flash chromatography, on silica (10 g), eluting with methanol/dichloromethane (0-15%) to give the title compound (23 mg, 26%); Mass Spectrum: M+H+ 587.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)[C:18]3=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[C:16]=2[C:48]#[N:49])=[CH:11][C:10]=1[CH3:50])C1C=CC=CC=1.C1CC=CCC=1>[Pd].CO.C(Cl)Cl>[C:48]([C:16]1[C:17]([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)=[C:18]2[C:23]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[N:22][NH:21][C:19]2=[N:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:50])[CH:11]=1)#[N:49]
Reactant: Cc1cc(-c2nc3[nH]nc(-c4ccco4)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: C1=CCC=CC1
Product: Cc1cc(-c2nc3[nH]nc(-c4ccco4)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)ccc1O
Yield: 49.9 %

Procedure:
To a solution of 2.12 g (3.2 mmol) of tert-butyl 4-(4-(6-(4-(benzyloxy)-3-methylphenyl)-5-cyano-3-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate in a MeOH/CH2Cl2 mixture are added 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene. The mixture is refluxed for 18 h, then 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene are added, and the mixture is refluxed for an additional 24 h, 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene are added and the mixture is again refluxed for 24 h. The mixture is then concentrated, dissolved in dichloromethane, filtered on Celite, then concentrated. The residue is purified by chromatography on silica (MeOH gradient in dichloromethane: 0 to 3%) to give 0.92 g (50%) of tert-butyl 4-(4-(5-cyano-3-(furan-2-yl)-6-(4-hydroxy-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate in the form of yellow crystals.
Reaction SMILES: [Cl:1][Sb-:2]([Cl:7])([Cl:6])([Cl:5])([Cl:4])[Cl:3].[CH3:8][O+](C)C.[Cl:12][C:13]1[S:17][N:16]=[C:15]([Cl:18])[C:14]=1[Cl:19]>>[Cl:1][Sb-:2]([Cl:7])([Cl:6])([Cl:5])([Cl:4])[Cl:3].[CH3:8][N+:16]1[S:17][C:13]([Cl:12])=[C:14]([Cl:19])[C:15]=1[Cl:18]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: C[O+](C)C
Agent: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl
Product: C[n+]1sc(Cl)c(Cl)c1Cl

Procedure:
Trichloroisothiazole (10 ml) and trimethyloxonium hexachloroantimonate (7.9 g, 0.02 mol) were heated at 90° for 30 min. After cooling either (150 ml) was added and the solid collected to yield 7.8 g (73%) of product, mp >240. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[C:13]([CH3:17])([CH3:16])[C:12]3=[N:18][N:19]=[C:20]([CH3:21])[N:11]3[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3=[N:18][N:19]=[C:20]([CH3:21])[N:11]3[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2(C)C
Agent: B
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)CC2(C)C
Yield: 10.4 %

Procedure:
To a THF (5 ml) solution of 6-(4-chlorophenyl)-1,4,4-trimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one of (51 mg, 0.14 mmol) was added BH3-THF complex (1 mL, 1M in THF) drop-wise at 0° C. The resulting mixture was heated at reflux overnight, then the mixture was concentrated in vacuo and the residue was purified by Prep-TLC (silica-gel, DCM:methanol=10:1) to give 6-(4-chlorophenyl)-1,4,4-trimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a white solid (5.0 mg, yield 10.4%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[CH2:13][CH2:12][C@H:11]3[C@H:7]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[CH2:23][C:22]([CH3:27])([CH3:26])[CH2:21][C:20]3=[O:28])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][N:37]([CH3:41])[C:38]([Cl:40])=[O:39].Cl>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[ClH:40].[CH3:36][N:37]([CH3:41])[C:38](=[O:39])[O:1][C:2]1[C:14]2[CH2:13][CH2:12][C@H:11]3[C@H:7]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:20](=[O:28])[CH2:21][C:22]([CH3:26])([CH3:27])[CH2:23][C:24]3=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)N(CCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)CC(C)(C)CC1=O
Reaction time: 8 h
Yield: 62.5 %

Procedure:
5.0 g (13.0 mmol) of rac-cis-1-[4-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione were dissolved in 250 ml of toluene. The solution was treated with 2.76 g (3.8 ml, 27 mmol) of triethyl-amine and 1.68 g (1.43 ml, 16 mmol) of dimethylcarbamoyl chloride and 250 mg of 4-dimethylaminopyridine and stirred under an argon atmosphere overnight in an oil bath at an oil bath temperature of 110°. After cooling the organic phase was washed in succession with water, sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated. The resulting brown oil (6.5 g) was chromatographed over a 30-fold amount of silica gel. The uniform eluates obtained in a thin-layer chromatogram using methylene chloride/ethyl acetate 1:1 were pooled and evaporated. The yellow oily base obtained (4.0 g) was converted into the hydrochloride in the usual manner, whereby there were obtained 4.0 g (62%) of rac-cis-3 -[4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-butyl]-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate hydrochloride as yellowish crystals of m.p. 190°-192° (dec.).
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[C:32]([O:36][C:37]([NH:39][C:40]([CH3:45])([CH3:44])[C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[CH3:45][C:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:44])[C:41]([NH:1][C@H:2]([CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4])=[O:42]
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@H](N)CCOc3ccccc3)C2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 8 h

Procedure:
(4S,5R)-7-((R)-2-amino-4-phenoxybutanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (55 mg; 0.130 mmol) was solubilised in acetonitrile (0.5 ml). 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (27 mg; 0.130 mmol) was added followed by diisopropylethylamine (0.091 ml; 0.522 mmol). The solution was stirred at RT for 5 minutes before ®T3P (50% solution in ethyl acetate) (0.152 ml; 0.261 mmol) was added. The mixture was stirred overnight, then concentrated in vacuo and purified by chromatography on silica eluting with 0-10% MeOH in TBME with ammonia to yield tert-butyl 2-methyl-1-((R)-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxo-4-phenoxybutan-2-ylamino)-1-oxopropan-2-ylcarbamate.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=2[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH2:19][OH:20])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=2[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH:19]=[O:20])=[O:13])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1S(=O)(=O)c1ccccc1)N1CCCC1CO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=CC1CCCN1C(=O)c1ccccc1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
0.6 g (1.7 mmol) of 1-[2-(phenylsulfonyl)benzoyl]-2-pyrrolidinemethanol in 0.73 ml (10 mmol) of dimethylsulfoxide (DMSO) and 20 ml methylene chloride was cooled to -70° C. 1.0 ml (6.8 mmol) of trifluoroacetic anhydride (TFAA) as added such that the temperature remained below -50° C. The reaction mixture was then stirred for 2 hours at between -50° and -70° C. 1.9 ml (14 mmol) of triethylamine was added and the mixture allowed to warm to 0° C. The reaction was quenched with water and the mixture was dried and evaporated to give an oil which was chromatographed on silica gel with chloroform to yield 0.2 g (34%) of the title compound. 1H NMR (CDCl3) δ: 9.70(m,1H); 8.10-8.20(m,3H); 7.20-7.70(m,6H); 4.70(m,1H); 3.30-3.50 (m,2H); 1.70-2.30(m,4H). High Resolution Mass Spectrum: m/e=344.0951±0.6 ppm (calculated for C18H18NO4S).