Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:3][CH:2]=1.Cl.[CH2:17](OC=N)C.N>ClCCl>[NH:14]1[CH2:13][CH:12]([CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[N:15]=[CH:17]1
Reactant: CCOC=N
Reactant: NCC(N)Cc1ccnc2ccccc12
Agent: Cl
Agent: N
Solvent: ClCCl
Product: C1=NC(Cc2ccnc3ccccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To 3-Quinolin-4-yl-propane-1,2-diamine (0.080 g, 3.98 mmol) in 5 ml of dry dichloromethane, formimidic acid ethyl ester hydrochloride (0.174 g, 7.36 mmol) (Ohme, R. et al. Angew.Chem.Int.Engl.Ed. 1967, 6, 90.) was added. The reaction mixture was stirred overnight at room temperature. Aqueous ammonia (2 ml) was added to he reaction mixture and was partitioned between EtOAc (2×5 ml) and water. The organic layer was dried, filtered and concentrated to give 0.084 g (110%) of the product as a syrup.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21]CC)=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.CN(C)C(=O)C.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][NH:37]1.[OH-].[Na+]>CCO.C1COCC1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:37]3[CH2:38][CH2:39][C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:36]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:19]([OH:21])=[O:20])([CH3:28])([CH3:26])[CH3:27]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1cc2nc(N3CCc4ccccc4C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (25 mg, 50 μmol), N,N-dimethylacetamide and 1,2,3,4-tetrahydroisoquinoline (50 μL). The reaction was heated to 100° C. for 30 min. Then THF (1 mL), EtOH (absolute, 500 μL), and 5 M aq NaOH (500 μL) were introduced. The reaction was heated for another 30 min at 100° C. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C29H29ClN2O3S: 521.2, 523.2 (M+H+); Found: 521.2, 523.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 7.71-7.47 (m, 4H), 7.38 (s, 1H), 7.30-7.22 (m, 4H), 5.17 (s, 1H), 4.79 (s, 2H), 3.84 (t, J=6.0 Hz, 2H), 3.09 (t, J=6.0 Hz, 2H), 2.54 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][C:38](Cl)=[O:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].N1C=CC=CC=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)=[O:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)Cc2ccc(OC)c(OC)c2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the preparation of example 46, 100 mg (0.283 mmol) of the compound from example 42A are reacted with 182 mg (0.849 mmol) of 3,4-dimethoxyphenylacetyl chloride and 0.23 ml (2.84 mmol) of pyridine in 6 ml of tetrahydrofuran.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(OC(C)(C)C)=O)[C:18]1=[O:19])(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:18]1=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)OC(C)(C)C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCN)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-3-(N-t-butyloxycarbonyl-6-aminohexyl)-7-methylxanthine (1.37 g) in dichloromethane (30 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (20 ml), with water (20 ml), with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine (1.073 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:55][CH:56]1[CH2:60][CH2:59][C:58](=[O:61])[O:57]1)(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH3:35])[CH2:55][CH:56]4[CH2:60][CH2:59][C:58](=[O:61])[O:57]4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C1CCC(COS(=O)(=O)C(F)(F)F)O1
Reactant: CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CC1CCC(=O)O1)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in CH3CN (5 mL) was added DIEA (70 mg, 0.54 mmol) and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate (66.5 mg, 0.27 mmol). The resulting solution was stirred overnight at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 37 mg (31%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 24) [M+H]+=657.2, RT=1.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.2, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.24-5.17 (m, 2H), 4.58-4.54 (m, 1H), 4.41-4.38 (m, 1H), 3.98-3.95 (m, 1H), 3.16-3.03 (m, 1H), 2.69-2.55 (m, 4H), 2.46-2.44 (m, 2H), 2.26 (s, 3H), 2.24-2.16 (m, 1H), 1.88-1.83 (m, 1H), 1.79-1.71 (m, 2H), 1.48-1.44 (m, 1H), 1.29-1.21 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=1.ClC(OCC)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C(#N)C.O>[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:26]=[N+:27]=[N-:28])=[O:17])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Triethylamine (8.5 mL, 60 mmol) was added slowly into the mixture of 3-p-tolyl-acrylic acid (8.3 g, 50 mmol) in 40 mL of acetonitrile followed by drop-wise addition of ethyl chloroformate (5.3 mL, 55 mmol) at 0° C. The solution was stirred for 2 h at this temperature. Sodium azide (6.5 g, 100 mmol) in 50 mL of water was added slowly to the above solution at 0° C. and the mixture was kept stirring for 1 h. Cold water was added and the precipitate was filtered and washed with cold water. The solid product (7.66 g, 82% yield) was obtained after being dried under vacuum. 1H-NMR (300 MHz, CDCl3) δ 7.72 (d, 1H), 7.44 (d, 2H), 7.21 (d, 2H), 6.38 (d, 1H), 2.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:38][C:39]1([F:45])[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40]1
Reactant: FC1(F)CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(F)(F)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4,4-difluoropiperidine according to conditions described in general procedure C. Mp: 172-174° C.; 1H NMR (400 MHz, CDCl3) δ 1.63-1.71 (m, 6 H), 1.86-1.91 (m, 4 H), 3.28 (t, J=5.8 Hz, 4 H), 3.77 (s, 4 H), 6.07 (d, J=5.8 Hz, 1 H), 6.75-6.79 (m, 1 H), 6.98 (d, J=8.0 Hz, 1 H), 7.29-7.31 (m, 2 H), 7.49-7.60 (m, 2 H), 7.90-7.99 (m, 3 H), 8.12 (s, 1 H), 8.17 (d, J=5.5 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([O:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:37])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Yield: 52.5 %

Procedure:
Reaction of 3.5 g of N-tert.-Butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid and 2.9 g of (L)-proline benzyl ester hydrochloride according to the procedure described for example 91b gave 3.0 g (52%) of the title compound as a yellow oil. (+)-APCI-MS: 505 (MNa+).
Reaction SMILES: Cl.C(OC([NH:9][C@@:10]1([C:34]([OH:36])=[O:35])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C@@H:14]([NH:26][C:27](=[O:30])[CH2:28][OH:29])[C@@H:13]2[C@H:11]1[C@H:12]2[C:31]([OH:33])=[O:32])=O)(C)(C)C>O1CCOCC1.O>[ClH:24].[NH2:9][C@@:10]1([C:34]([OH:36])=[O:35])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C@@H:14]([NH:26][C:27](=[O:30])[CH2:28][OH:29])[C@@H:13]2[C@H:11]1[C@H:12]2[C:31]([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](NC(=O)CO)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](NC(=O)CO)[C@H]1OCc1ccc(Cl)c(Cl)c1
Yield: 133.3 %

Procedure:
Add 4N hydrogen chloride (3.0 mL, 12.0 mmol) in 1,4-dioxane to a mixture of (1S,2R,3R,4S,5R,6S)-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]-4-[(2-hydroxyacetyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.032 g, 0.06 mmol) in water (0.3 mL). Wash the solid with acetonitrile and diethylether on a fritted funnel Sequentially wash the solid with acetonitrile and diethylether and then further dry in a vacuum oven overnight at 50° C. to provide the title compound as a white solid (0.018 g, 0.04 mmol, 65%). MS (m/z): 433 (M+H).
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:47])[N:38]=[CH:39][C:32]=23)[C:26](OC)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(Cl)Cl>[Si:12]([O:19][CH:20]1[CH2:21][N:22]([CH2:24][C@H:25]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=4[Cl:46])[N:38]=[CH:39][C:32]=23)[C:26]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)=[O:27])[CH2:23]1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@H](CN1CC(O[Si](C)(C)C(C)(C)C)C1)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Reactant: Nc1ccccn1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)C(=O)Nc2ccccn2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
Trimethylaluminium (0.362 mL, 0.72 mmol) was added to a solution of pyridin-2-amine (68.1 mg, 0.72 mmol) in toluene (8 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate BJ1) (200 mg, 0.36 mmol) in toluene (4 mL) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated. The residue was neutralised to pH 7 with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (151 mg, 67.9%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][C:21]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[C:22]#[CH:23].CN(C)C=O.C(N(CC)CC)C>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CO.ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:23]#[C:22][C:21]([CH3:24])([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH3:20])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(C)O[Si](C)(C)C)nc21
Temperature: 90 °C
Yield: 62.3 %

Procedure:
In a 2 l three-necked flask, 40.7 g of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxamide (0.145 mole) and 56.2 ml of [(1,1-dimethyl-2-propynyl)oxy]trimethylsilane (0.290 mol) are successively introduced into a mixture of 365 ml of dimethylformamide and 365 ml of triethylamine. The reaction mixture is sparged with argon for 15 minutes and then 0.983 g of CuI (5.16 mmol) and 5.1 g of bis(triphenylphosphine) palladium(II)dichloride (7.2 mmol) are added successively. The reaction mixture is heated for 15 hours at 90° C. and then concentrated under a reduced vacuum. The residue is taken up in 500 ml of an ethyl acetate/NaHCO3aq mixture (V/V=1/1) and filtered over a celite buffer, rinsing being carried out with ethyl acetate. The aqueous phase is extracted with dichloromethane (3×50 ml) and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The reaction crude is purified by silica column chromatography (elution with a dichloromethane:ethyl acetate gradient, 80:20 to 50:50, and then a dichloromethane:methanol gradient, 95:5 to 90:10) so as to give 36.2 g of expected product (yield=62.3%) and also 7.4 g of desilylated product described in the next step (yield=15.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](F)[C:5]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[NH4+:20].[NH4+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:20])[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
6.0 g (27.5 mmol) of 3,5-difluoro-2-nitro-benzoic acid methyl ester was dissolved in DMF and treated with 2.9 g (30.25 mmol) of ammonium carbonate. The reaction was heated at 60° C. for 6 h. Water was added to the reaction mixture. The solid produced was collected by filtration and washed with water to produce 3-amino-5-fluoro-2-nitro-benzoic acid methyl ester. LCMS: 215 (M+1)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH2:27])[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: COC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: COC(=O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (αS)-α-amino-cyclopropanepropanoic acid methyl ester hydrochloride (1:1) (CAN 206438-31-5) as starting materials, and isolated (80 mg, 75%) as yellow oil; LC-MS (UV peak area, ESI) 100%, 360.1920 (M+H).
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(Nc2ncnc3[nH]c4ccccc4c23)cc1
Yield: 18.8 %

Procedure:
4-Chloroindolo[2,3-d]pyrimidine hydrochloride (R. G. Glushkov et. al., Khim.-Farm. Zh., 1967, 1(9), 25-32) (240 mg, 1 mmol) and aniline (0.27 mL, 3 mmol) in ethanol (1 mL) are heated under reflux for 6 h. The solvent is evaporated under reduced pressure, and the residue triturated with EtOAc to afford a tan powder which is filtered, and washed with cold ethanol. Recrystallization from acetone/pet. ether gives 4-anilinoindolo[2,3-d]pyrimidine (49 mg, 19%). 1H NMR (DMSO) δ1H, s), 8.84 (1H, s), 8.43 (1H, s), 8.37 (1H, d, J=8.0 Hz), 7.74 (2H, d, J=7.7 Hz), 7.52-7.08 (6H, m).
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([NH2:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].C(OCC)(=O)C.C(#N)C.[Cu]I>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([NH2:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CC(C)(N)C1CCNCC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(C(C)(C)N)CC5)ccc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.15 g, 0.30 mmol) in dimethyl sulfoxide (5 mL) was added 2-(piperidin-4-yl)propan-2-amine dihydrochloride (0.19 g, 0.90 mmol), copper(I) iodide (0.005 g, 0.030 mmol), potassium carbonate (0.25 g, 1.80 mmol), and L-proline (0.007 g, 0.057 mmol). The light yellow reaction mixture was heated to 100° C. After 24 h, an additional portion of L-proline (0.007 g, 0.057 mmol) was added and heating continued. After an additional 5 h, the reaction mixture was allowed to cool to room temperature and was diluted with ammonium hydroxide solution and ethyl acetate. The organic phase was separated and washed with saturated sodium bicarbonate solution (×2), brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Biotage, 10 g SiO2 column, 10% methanol/dichloromethane to 3 M ammonia in methanol/dichloromethane elute) provided an oil. The oil was dissolved in aqueous acetonitrile and lyophilized to afford 0.070 g (45%) of the product as tan solid:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17](OC)=[O:18])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][OH:24].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([NH:23][OH:24])=[O:18])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NO)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To methyl 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.22 g, 0.73 mmol) in methanol (10 mL) were added hydroxylamine (2 mL, 30.3 mmol, 50% in water) and sodium hydroxide (2.0 mL. 2.0 mmol, 1 N aqueous solution). The resulting solution was stirred for 16 h at ambient temperature. After addition of 1N hydrochloric acid (2.0 mL. 2.0 mmol) the product precipitated out. It was collected by filtration, washed with water and ethyl acetate, and dried in vacuo to provide the title compound as a solid (0.18 g, 82% yield). 1H NMR (DMSO-d6) δ: 13.19 (s, 1H), 11.41 (s, 1H), 9.17 (s, 1H), 8.39 (s, 1H), 7.71 (d, 1H, 7.34 (t, 2H, 7.16 (t, 2H) 6.68 (d, 1H), 5.54 (s, 2H). LCMS (APCI, M+H+): 302.1. HRMS calcd for C15H12FN3O3 (M+H) 302.0936, found 302.0935. HPLC: 100% purity.
Reaction SMILES: COC([CH:5]1[CH:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:7]=2[C:6]1=[O:19])=O.O>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6](=[O:19])[CH2:5][CH:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1
Reactant: COC(=O)C1C(=O)c2ccc(Cl)cc2NC(=O)C1C
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)c2ccc(Cl)cc2NC1=O
Temperature: 230 °C

Procedure:
To a solution of 8-chloro-3-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (iii-i) (0.2 g, 0.7 mmol) in DMF (2 mL) was added H2O (0.3 mL) and the reaction mixture heated to 230° C. in a microwave reactor for 5 minutes. H2O (20 mL) was added to the reaction mixture and the resulting precipitate was filtered and washed with H2O. The solid was dried under reduced pressure at 40° C. for 16 h to afford iv-i (0.12 g, 77%) as a white solid: MS m/z═224 (M+H).