Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:17]1[CH2:22][CH2:21]OC[CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCC1>CN(C=O)C>[N:17]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]2[CH2:15][CH2:14]2)[CH2:18][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CC1
Reactant: CN1CCOCC1
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC1)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-2-cyclopropylacetic acid (2.0 g, 9.30 mmol), which is commercially available, and NMM (3.07 mL, 27.9 mmol) was mixed in DMF (20 mL). The mixture was cooled to 0° C. and TBTU (3.34 g, 10.42 mmol) was added. After 10 min at rt was azetidine (1.6 mL, 23.7 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (300 mL). The organic phase was washed with NaHCO3 (saturated, 150 mL) and brine (150 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (2.04 g, 86%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.39, 0.44-0.63, 1.09, 1.43, 2.31, 3.84, 3.93-4.46, 5.30. Total no of protons: 22.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15]>CN(C=O)C>[CH2:12]([O:13][C:14](=[O:16])[CH2:15][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:11]
Reactant: CC(=O)OCCBr
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccncc1
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL of DMF was added 3.4 g (36.0 mmol) of 4-hydroxypyridine. The mixture was stirred 10 minutes then added to a solution of 3.3 mL (30.0 mmol) of bromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72 hours at rt. then concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water and washed with saturated aqueous NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using MeOH/chloroform as eluent and concentrated to dryness to yield 510 mg (9.4%) of the desired product as a tan oil. 1H—NMR is consistent with structure. MS (ion spray) 182.1 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:49])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][OH:48])[CH2:15]2)=[CH:10][CH:9]=1>CCOC(C)=O.CCCCCCC>[CH3:1][O:2][CH2:3][C@H:4]([CH3:49])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:47][O:48][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CO)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](COS(C)(=O)=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
The title compound is prepared according to general procedure F starting from 1.0 mmol of [(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-methanol. Rf=0.45 (EtOAc/heptane 2:1); Rt=5.52 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[OH:8][C:7]1[C:2]2=[N:1][C:9]([CH3:10])=[C:12]([CH2:17][CH2:16][OH:15])[C:13](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2c(O)cccn2c(=O)c1CCO

Procedure:
During chemical development this process was altered. 2-Amino-3-hydroxypyridine was reacted with 2-acetyl-butyrolactone in the presence of p-toluenesulfonic acid in xylene to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; this product proved to be poorly soluble in xylene resulting in deposit formation on the wall of the reaction vessel and discoloration of the reaction mixture to black.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-chloroaniline (12.8 g, 100.3 mmol), ethyl bromoacetate (12.2 mL, 110.4 mmol). and potassium carbonate (13.9 g, 100.3 mmol) in acetonitrile (330 mL) was heated overnight at 80° C. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and triturated DCM and the resulting solid was filtered to yield ethyl 2-((4-chlorophenyl)amino)acetate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C@H:15]1[CH2:20][C:19]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:21]2[C:19]3[CH2:20][C@H:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)[CH2:16][O:17][C:18]=3[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CO3)CC1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
A mixture of 4-trifluoromethylbenzoic acid (195 mg, 1.02 mmol) in thionyl chloride (5 mL) was heated at 50° C. for 20 min and then to reflux for 10 min. The mixture was allowed to cool after which the excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to an ice-cooled solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230 mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrous methylene chloride (20 mL) with stirring. The reaction mixture was allowed to reach room temperature and was washed with a saturated NaHCO3 solution. After drying (MgSO4) and evaporation of the solvent in vacuo, a crude product was obtained which was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3). This procedure gave 214 mg (55% yield) of the title compound as a white solid: mp 212–214° C.; [α]22D−73° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 419 (100, M+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].F[B-](F)(F)F.[CH3:14][O+](C)C>C(Cl)Cl>[CH3:14][O:8][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:1]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCCN1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCCCC1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of azepan-2-one (1.13 g, 10.0 mmol) in DCM (10 mL) in a 40 mL screw cap vial was added freshly prepared trimethyloxonium tetrafluoroborate (1.57 g, 10.59 mmol). The resulting suspension was shaken overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 ml) (caution: vigorous CO2 evolution). More aqueous sodium hydrogen carbonate was added until the aqueous layer reached pH 8. The organic layer was removed and the aqueous layer extracted with DCM (5 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield (E)-7-methoxy-3,4,5,6-tetrahydro-2H-azepine (1.2 g, 95%) as a clear oil. LCMS (+ESI) m/z 128.2 [M+H]+. 1H-NMR (CDCl3) δ 3.60 (s, 3H), 3.45 (m, 2H), 2.40 (m, 2H), 1.80 (m, 2H), 1.60-1.50 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+].N#N>O.C(OCC)(=O)C.CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[CH:16]=[CH:17][C:18]([C:31]2[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=2)=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Fc1cnc(Cl)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(-c2ncc(F)cn2)cc1
Temperature: 70 °C
Yield: 56.7 %

Procedure:
A mixed DMF/H2O (5 mL/5 mL) solution of (S,S)-5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (800 mg, 2 mmol), 2-chloro-5-fluoro-pyrimidine (340 mg, 2.6 mmol), K2CO3 (552 mg, 4 mmol) and Cl2Pd(dppf)CH2Cl2 (160 mg) was evacuated and recharged with N2 several times. The reaction was heated at 70° C. over 18 hrs. After cooling down to rt, 40 mL ethyl acetate and 10 mL water was added. The mixture was filtered through a pad of Celite and washed with additional ethyl acetate. The separated organic layer was dried (MgSO4) and concentrated. The crude was purified on silica gel column eluting with 50% ethyl acetate/hexanes to yield the title compound (420 mg) as a light yellow solid.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O1CCOCC1.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](=[O:24])[NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CN
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 20 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 100 ml. dioxane is added to 4.9 g. freshly prepared ethyl glycinate in 300 ml. of methylene chloride containing 1 g. of 4-(dimethylamino)pyridine and 10 ml. of triethylamine. After 16 hours at room temperature the reaction is refluxed for 2 hours, cooled and filtered. The mother liquor is extracted with water and 10% hydrochloric acid. The solution is dried and concentrated in vacuo to an amber liquid. A sample is chromatographed on silica, appropriate fractions are pooled and evaporated to yield a solid which is recrystallized to a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(Cl)Cl.[CH2:25]([N:27](CC)CC)C>CC(N(C)C)=O.[C-]#N.[Zn+2].[C-]#N>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:25]#[N:27])=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CCN(CC)CC
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 85 °C
Yield: 88 %

Procedure:
To a suspension of 6-[(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl]quinoline (1.0 g, 2.93 mmol) in DMAC (70 ml) were added zinc cyanide (413 mg, 3.52 mmol). The reaction mixture was degassed then PdCl2(dppf).CH2Cl2 (240 mg, 0.29 mmol) was added followed with triethylamine (0.828 ml) at R.T. The reaction mixture was degassed again. After heating at 85° C., the reaction mixture was filtered through a celite pad and washed with 5.0 ml of CH2Cl2. The solvents were concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 1-3% 7N N3 in MeOH:CH2Cl2 to give the desired product (740 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.28 (s, 2H) 7.55 (dd, J=8.34, 4.29 Hz, 1H) 7.81 (dd, J=8.72, 2.15 Hz, 1H) 7.99-8.04 (m, 2H) 8.33-8.37 (m, 1H) 8.91 (dd, J=4.04, 1.77 Hz, 1H) 9.41 (s, 1H) APCI (Mz+1) 288.2
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[C:3]=12.[CH3:21][C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:53]>CCCCO>[ClH:53].[NH2:28][C:22]1([CH3:21])[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[C:7]([F:8])=[CH:6][N:5]=[C:4]3[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[C:3]=23)[CH2:23]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCNC1
Reactant: ClCCl
Reactant: O=C(Nc1c[nH]c2ncc(F)c(F)c12)c1cccnc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCCN(c2c(F)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Product: Cl
Temperature: 150 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A mixture of N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (50 mg, 0.18 mmol; Example 13, Step D), tert-butyl 3-methylpiperidin-3-ylcarbamate (78 mg, 0.37 mmol, Example C) and DIEA (0.032 mL, 0.182 mmol) in n-BuOH (1 mL) was stirred at 150° C. (bath) for 24 hours in a sealed tube. The solvent was removed, and the resulting residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH3CN/water gradient; 30 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in MeOH (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give N-(4-(3-amino-3-methylpiperidin-1-yl)-5-fluoro-1H-pyrrolo [2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.050 g, 56%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 11.03 (s, 1H), 9.49 (s, 1H), 8.95 (m, 2H), 8.27 (s, 2H), 8.18 (d, 1H), 7.93 (m, 1H), 7.53 (d, 1H), 3.43 (m, 1H), 3.36 (m, 2H), 3.04 (m, 1H), 1.71 (m, 1H), 1.51 (m, 2H), 1.31 (m, 1H), 1.22 (s, 3H). LCMS (APCI+) m/z 369(M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][C:11]=2[CH:36]=1)C.[OH-].[Na+].Cl>C(O)C>[C:32]([O:31][C:29]([N:17]([CH:13]1[CH2:12][C:11]2[CH:36]=[C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])[CH:8]=[CH:9][C:10]=2[CH2:16][CH2:15][CH2:14]1)[CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (3.60 g) in ethanol (20 ml) was added 1N sodium hydroxide (7 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was acidified with hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (3.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:67])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]#[CH:66])=[CH:59][CH:58]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:55])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[NH:27][C:28](=[O:47])[NH:29][C@H:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].[N:68]([CH2:71][CH2:72][CH2:73][NH2:74])=[N+:69]=[N-:70]>C1COCC1.O.C(Cl)Cl.[Cu].[O-]S([O-])(=O)=O.[Cu+2]>[NH2:74][CH2:73][CH2:72][CH2:71][N:68]1[CH:66]=[C:65]([CH2:64][O:63][C:60]2[CH:61]=[CH:62][C:57]([CH2:56][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:55])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]([C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[NH:27][C:28](=[O:47])[NH:29][C@H:30]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:13][C:9]3[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:67])[CH:12]=[CH:11][N:10]=3)=[CH:58][CH:59]=2)[N:70]=[N:69]1
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=NCCCN
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCN)nn2)cc1)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
To a solution of (14S,18S)-tri-tert-butyl 1-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (250 mg, 0.266 mmol) and 3-azidopropan-1-amine (200 mg, 2.0 mmol) in THF (5.0 mL) and water (1.0 mL) was added copper powder (17 mg) and 1 N CuSO4 (0.05 mL). The mixture was stirred at room temperature for 6 hrs under nitrogen, diluted with DCM, washed with aqueous saturated solution of EDTA. The solvent was evaporated under reduce pressure to afford a residue, which was purified by Biotage SP4 to afford (14S,18S)-tri-tert-butyl 2-(4-((1-(3-aminopropyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-1-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (158 mg, 57%) as a yellow oil. MS (ESI), 520.4 (M/2+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]1([NH:40]O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:40][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: ONC1CCCCC1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(ONC1CCCCC1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-cyclohexylhydroxylamine hydrochloride (469 mg, 3.09 mmol) was added and the solution was stirred for 2 hours at room temperature. To the resulting solution was added water (15 mL). The insoluble material was filtered and dried to give the title compound (286 mg, 72% yield, m.p. 220° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:15][C:8]2=[CH:9][N:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:7]2[C:6]=1I)=[O:4].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[C:26](=O)([O-])[O-:27].[K+].[K+].O>COCCOC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:15][C:8]2=[CH:9][N:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:7]2[C:6]=1[C:19]1[C:18]([O:27][CH3:26])=[N:17][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: OB(O)c1ccccn1
Reactant: COC(=O)c1[nH]c2cnc(OC)cc2c1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1[nH]c2cnc(OC)cc2c1-c1cccnc1OC
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
3-Iodo-5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester C3 (0.3 g, 0.9 mmol) was diluted with 1,2-dimethoxyethane (5 mL) and to the resulting solution was added PdClz2 (dppf)2 (0.074 g, 10 mol %). The reaction was heated to 90° C. and allowed to stir at this temperature for 30 minutes. Pyridyl boronic acid (0.415 g, 2.7 mmol), potassium carbonate (0.621 g, 5 mmol), and water (0.3 mL) were then added to the reaction mixture in three portions over 5 minutes. The resulting reaction allowed to stir at 90° C. for an additional minutes, then the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered through a celite plug. The filtrate was concentrated in vacuo and the resulting residue was purified using flash chromatography to provide 5-methoxy-3-(2-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester C4 (0.075 g, 27% yield). MS: 314.2 (M+H)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[C:36]([C:43]2[C:52]3[C:47](=[CH:48][C:49]([C:53](O)=[O:54])=[CH:50][CH:51]=3)[N:46]=[CH:45][CH:44]=2)=[C:37]2[CH2:42][CH2:41][CH2:40][N:38]2[N:39]=1>ClCCl>[CH:23]1([NH:28][C:53]([C:49]2[CH:48]=[C:47]3[C:52]([C:43]([C:36]4[C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=5)=[N:39][N:38]5[CH2:40][CH2:41][CH2:42][C:37]=45)=[CH:44][CH:45]=[N:46]3)=[CH:51][CH:50]=2)=[O:54])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1CCCC1)c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (53 mg, 0.30 mmol), HOBT, (24 mg, 0.28 mmol), cyclopentylamine (0.03 mL, 0.30 mmol), and 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid (90 mg, 0.25 mmol) in dichloromethane (1 mL) is stirred room temperature for 18 h. The mixture is concentrated in vacuo and the residue chromatographed on SiO2 to yield the title compound, 31 mg (31%,) as a white solid.
Reaction SMILES: Cl.CO[C:4]([C:6]1[S:7][CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11])=[O:5].COC(C1SC=C(C)C=1N=C=S)=O.COC(=O)C[N:30]1[C:35](=[O:36])[C:34]2SC=C(C)C=2[NH:32][C:31]1=S>>[CH3:12][C:9]1[C:10]2[N:11]=[C:31]3[NH:30][C:35](=[O:36])[CH2:34][N:32]3[C:4](=[O:5])[C:6]=2[S:7][CH:8]=1
Reactant: COC(=O)Cn1c(=S)[nH]c2c(C)csc2c1=O
Reactant: COC(=O)c1scc(C)c1N
Agent: COC(=O)c1scc(C)c1N=C=S
Agent: Cl
Product: Cc1csc2c(=O)n3c(nc12)NC(=O)C3

Procedure:
The starting material can be prepared in an analogous manner to Example 1 starting from 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester hydrochloride via 4-methyl-3-isothiocyanato-2-thiophenecarboxylic acid methyl ester (70 g, melting point 227°-228°) and 1,4-dihydro-7-methyl-4-oxo-2-thioxothieno[3,2-d]pyrimidine-3(2H)-acetic acid methyl ester (69 g, melting point 227°-228°); yield 68.9 g, melting point 131°-132°.