Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]([NH2:30])=[N:8][C:9]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[N:14]=3)=[N:10][C:11]=2[NH2:12])[CH2:4][CH2:3][CH2:2]1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:12][C:11]1[N:10]=[C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:8]=[C:7]2[C:6]=1[N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:36](=[O:37])[NH:30]2
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NC1CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C3CCC3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
133 mg (0.26 mmol) of the compound from example 65A were initially charged in dimethylformamide (1.4 ml), then 213 mg (1.32 mmol) of N,N-carbonyldiimidazole and 0.44 ml (3.16 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. Thereafter, another 200 mg (1.23 mmol) of N,N-carbonyldiimidazole were added and the mixture was again stirred at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 79 mg (68% of theory) of the title compound in solid form.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2F)=[O:23])[CH2:21][CH2:20]1.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[O:23])[CH2:20][CH2:21]1
Reactant: O=C(c1cccc(F)c1F)C1CC1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(F)cccc4C(=O)C4CC4)cc23)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (70 mg; 0.290 mmol) and 63 mg (0.346 mmol) of cyclopropyl(2,3-difluorophenyl)methanone were added to a solution of 81 mg (0.723 mmol) of tert-butoxy potassium in 6 ml of N,N-dimethylacetamide and the mixture was stirred at 110° C. for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=10:1) to give 36 mg (yield: 31%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=1.[OH-].[K+].O>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[C:11]([CH3:16])[CH:10]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(Br)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(COc1ccc(Br)cc1C)OC
Temperature: 100 °C

Procedure:
Bromoacetaldehyde dimethylacetal (6.05 ml) was added to a stirred solution of 4-bromo-2-methylphenol (10.0 g) and KOH (5.0 g) in dry DMSO (40 ml). The solution was warmed to 100° C. for 4 hours. After this time the reaction mixture was cooled to room temperature and poured into water (200 ml). The aqueous layer was extracted with ether (2×100 ml). The combined organic layers were separated, washed with 2N aqueous NaOH (2×50 ml), dried over MgSO4, filtered, and the solvent removed under reduced pressure to afford a brown oil. Purification by MPLC (15% ethyl acetate/n-hexane) afforded 4-bromo-1-[(2,2-dimethoxyethyl)oxy]-2-methylbenzene as a colourless oil (6.24 g). 1H NMR (360 MHz,CDCl3)δ2.21 (3H, s), 3.46 (6H,s), 3.98 (2H, d, J=3.6 Hz), 4.69 (1H, t, J=3.6 Hz), 6.56 (1H, d, J=7.2 Hz), 7.26 (1H, d, J=7.2 Hz), 7.39 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].Cl[C:12]1[N:17]=[C:16]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:15]=[N:14][CH:13]=1.[F-].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:17]=1
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: O=S(=O)(Nc1cncc(Cl)n1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2cncc(NS(=O)(=O)c3ccccc3)n2)s1
Temperature: 160 °C
Yield: 4.7 %

Procedure:
A mixture of 2-acetamido-4-methylthiazole (891 mg), N-(6-chloropyrazin-2-yl)benzenesulfonamide (1.4 g), palladium acetate (94 mg), caesium fluoride (2.35 g), tri-tert-butylphosphine (0.34M in hexane, 2.4 mL) and DMSO (45 mL) was purged with nitrogen. The resultant mixture was stirred and heated to 160° C. for 3.5 hours. The bulk of the DMSO was evaporated and water (50 mL) was added. The resultant solid was filtered off, washed with water and dried under vacuum. A 19:1 mixture of dichloromethane and methanol was added and the mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica using a solvent gradient of 3% to 5% methanol in dichloromethane as eluent. There was thus obtained the title compound as a solid (95 mg); 1H NMR Spectrum: (DMSOd6) 2.20 (s, 3H), 2.49 (s, 3H), 7.60-7.70 (m, 3H), 8.06 (m, 2H), 8.11 (s, 1H), 8.47 (s, 1H), 11.68 (s, 1H), 12.27 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:32])[C:3]=1[OH:33].O[C@@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36]([O:38]C)=[O:37]>>[Br:32][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:33][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Sc3ccncc3)c3sc4ccccc4c23)cc1Br
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Sc3ccncc3)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-[6-(pyridin-4-ylsulfanyl)-benzo [b]naphtho[2,3-d]thiophen-11-yl]-phenol (Example 65) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO- d6); δ13.3 (broad singlet, 1 H), 8:45 (m, 2 H), 8.37 (d, J=8 Hz, 1 H), 7.99 (d, J=8 Hz, 1 H), 7.85 (dd, J=7, 2 Hz, 2 H), 7.77-7.74 (m, 1 H), 7.66-7.65 (m, 2 H), 7.50 (t, J 7 Hz, 1 H), 7.43-7.25 (m, 8H), 6.68 (d, J=8 Hz, 1 H), 5.35 (dd, J 8 ,2 Hz, 1 H), 3.43 (d, J=7 Hz, 2 H); MS [+FAB]: [(M+H)+], 739.9 (70%), 741.9 (100%), 743.9 (90%); MS High resolution (FAB)+ve, calc mass for C36H24Br2NO3S2 739.95644; measured mass 739.96224, mass deviation 5.80 mmu. Anal. Calc. for C36H23Br2NO3S2: C, 55.58, H, 3.11, N, 1.80. Found: C, 55.38, H, 3.37, N, 1.92.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CCN(CCCCc3c[nH]c4ccc(C(=O)O)cc34)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccc(O)cc4)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 4.04 g of 3-[4-(4-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid and 3.5 g of pyridine hydrochloride is stirred for 3 hours at 160°. Working up in the customary manner gives 3-[4-(4-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid.
Reaction SMILES: [H-].[Na+].CC[O:5]CC.N1C=CC=N1.[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>O1CCCC1>[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]([OH:5])=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)ccc1OCCCCl
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCCCCl
Reaction time: 0.25 h

Procedure:
To a stirred suspension under nitrogen of sodium hydride (6.4 g, 130 mmol, of about 50% oil dispersion-ether washed) in tetrahydrofuran (220 ml) was added pyrazole (4.4 g, 60 mmol) in tetrahydrofuran (60 ml), dropwise. After complete addition, the reaction was stirred for about 15 minutes, and then 4-(3-chloropropoxy)-3-methoxybenzaldehyde (24.5 g, 107 mmol) was added. The nitrogen was stopped and air was sparged into the reactor for about 3 hours. The reaction was then allowed to stir at ambient temperature open to the atmosphere for 6 hours. Water was added, the reaction was cooled in an ice bath, and concentrated hydrochloric acid (25 ml) was added dropwise. More water was added and the yellow solid that separated was collected to afford 16.2 g of product. The filtrate was then extracted with ethyl acetate to afford an additional 9.3 g. The samples were combined and recrystallized from acetonitrile to yield 12.6 g of a light, yellow solid, m.p.=154°-156° C. A 4.0 g sample was recrystallized from acetonitrile to yield 2.6 g of a yellow solid. This was combined with 0.4 g from another sample and recrystallized again from acetonitrile with charcoal treatment to afford 2.0 g of 4-(3-chloropropoxy)-4-methoxybenzoic acid as a yellow solid, m.p.=157°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:52]2[CH:53]=[CH:54][C:49]([CH2:48][C@H:47]([NH:62][C:34]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:37][CH2:38][C@H:13]([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]7[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=7)=[CH:12][CH:11]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH3:27])=[O:35])[C:46]([OH:45])=[O:63])=[CH:50][CH:51]=2)=[CH:56][CH:57]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (16 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 862.
Reaction SMILES: [Na].[F:2][C:3]([F:7])([F:6])[CH2:4][OH:5].[F:8][C:9]([F:29])([F:28])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH:20]3[CH2:22][C:23]4([CH2:26][CH:19]3[C:18]2=[O:27])[CH2:25][O:24]4)=[CH:13][CH:12]=1>O>[OH:24][C:23]1([CH2:25][O:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH2:26][CH:19]2[C:18](=[O:27])[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][C:9]([F:8])([F:28])[F:29])=[CH:16][CH:15]=3)[CH2:21][CH:20]2[CH2:22]1
Reactant: O=C1C2CC3(CO3)CC2CN1c1ccc(OC(F)(F)F)cc1
Reactant: OCC(F)(F)F
Agent: [Na]
Solvent: O
Product: O=C1C2CC(O)(COCC(F)(F)F)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A small piece of sodium was added to 2,2,2-Trifluoro-ethanol (20 mL), and the mixture was stirred at 80° C. for 5 minutes, then rac-(3aR,5S,6aS)-2-[4-(trifluoromethoxy)phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxiran]-1-one was added. The mixture was stirred for 6 h. The solution was then poured into water (25 mL) and extracted with ether (3×20 mL), dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to yield the title compound. 1H NMR (300 MHz, CDCl3): δ 7.66-7.63 (m, 2H), 7.20-7.17 (m, 2H), 4.13 (t, 1H, J=9.6 Hz), 3.86 (q, 2H, J=8.7 Hz), 3.71-3.61 (m, 3H), 3.22-3.17 (m, 1H), 3.05-2.99 (m, 1H), 2.38-2.33 (m, 1H), 2.09-1.76 (m, 4H); LC-MS: 414.1 [M+1]+.
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([N:15]([CH3:17])[CH3:16])[N:13]=2)[C:8](=[O:19])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:6]1)(C)(C)C>Cl>[CH3:16][N:15]([CH3:17])[C:12]1[N:13]=[C:14]2[C:9]([C:8](=[O:19])[C:7]([C:20]([OH:22])=[O:21])=[CH:6][NH:5]2)=[CH:10][C:11]=1[F:18]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N(C)C)c(F)cc2c1=O
Agent: Cl
Product: CN(C)c1nc2[nH]cc(C(=O)O)c(=O)c2cc1F

Procedure:
A solution of EXAMPLE 69A (155 mg) in 6M HCl (10 mL) was heated at 110° C. for 18 hours then cooled and filtered. NMR (300 MHz, CDCl3) δ 8.64 (d, 1H), 8.00 (d, 1H), 3.32 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH2:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:32][CH2:30][CH3:31])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CCN
Product: CCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and ethylamine gave 206. MS: (ESI+) 441.0
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1)[C:10]#[N:11].[NH2:26][NH2:27]>CCO.CC(O)=O>[NH2:11][C:10]1[NH:27][N:26]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:9]=1[C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1
Reactant: CC(C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)nc2s1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1nc2ccc(-c3c(-c4ccccc4)n[nH]c3N)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.4 %

Procedure:
To a solution of 3-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)-3-oxopropanenitrile (0.10 g, 0.282 mmol, 1.0 eq.) in EtOH (1 mL) and HOAc (2 mL) at 0° C. was added hydrazine (0.1 mL, 3.19 mmol, 11.3 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 88° C. for 5 hr and at 100° C. overnight. After cooling to room temperature and then to 0° C., water was added followed by concentrated aqueous NH4OH until pH was 10 by litmus paper. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(5-amino-3-phenyl-1H-pyrazol-4-yl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine as a light yellow solid (0.0014 g, 1.3% yield). LC/MS (MH)=369.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([O:19]C)=[O:18])=[CH:7][C:6]=2[CH:21]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([OH:19])=[O:18])=[CH:7][C:6]=2[CH:21]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CCC(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
In THF (36 ml)/methanol (36 ml) was dissolved methyl 7-bromo-1-isopentyl-2,3-dihydro-1-benzazepine-4-carboxylate (1.8 g). To the solution was added 1N sodium hydroxide solution (18 ml), and the mixture was stirred at room temperature for 24 hours. pH was adjusted to approximate 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-bromo-1-isopentyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.51 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:24]([O-:27])(=[O:26])[CH3:25].[K+]>CC#N.CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][O:27][C:24](=[O:26])[CH3:25])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)OCc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)N(C(C)=O)CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (7.0 g) was dissolved in a mixed solvent (50 ml) of CH3CN/DMF=1/1. Potassium acetate (12.0 g) was added and the mixture was stirred at 60° C. for 1 hr. CH3CN was evaporated under reduced pressure and AcOEt (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=1/0−10/1) to give 7.5 g of N-(1-acetyl-5-acetoxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: O.NN.CCO.O=C1C2C(=CC=CC=2)C(=O)[N:9]1[C@H:18]([C:20]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])=[N:28][C:27]2[C:26]([C:40]#[N:41])=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1)[CH3:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:9][C@H:18]([C:20]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])=[N:28][C:27]2[C:26]([C:40]#[N:41])=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1)[CH3:19]
Reactant: C[C@@H](c1nc2cccc(C#N)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C[C@H](N)c1nc2cccc(C#N)c2nc1-c1ccccc1S(C)(=O)=O
Yield: 93.4 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet, overhead stirrer and thermocouple was charged with hydrazine hydrate (381 mL, 783 mmol) and EtOH (3.0 L). To the solution was then added 2-((S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-3-(2-(methylsulfonyl)phenyl)quinoxaline-5-carbonitrile (378 g, 783 mmol) in one portion and heated to 80° C. The reaction was monitored by LC, and deemed complete once the reaction again reached 80° C. The reaction was cooled to room temp (20-21° C.), when DCM (3.0 L) and satd. NaHCO3 solution (600 mL) were added. After phase separation, the organic layer was washed with brine (2×600 mL), concentrated and dried under vacuum and N2 flow for 24 h to afford the product as a light yellow solid 257.7 g with 94.4% LC purity, (no R enantiomer detected) and 93% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.54 (m, 2H), 8.18 (dt, J=7.7, 1.5 Hz, 1H), 8.05 (dd, J=8.5, 7.4 Hz, 1H), 7.76-8.00 (m, 3H), 3.83-4.03 (m, 1H), 3.25-3.32 (m, 3H), 1.19-1.39 (m, 3H) Mass Spectrum (ESI) m/z=353.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:35]1[CH2:40][CH2:39][N:38](CCO)[CH2:37][CH2:36]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][CH2:25][N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OCCN1CCOCC1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCCN1CCOCC1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (25 mg, 0.054 mmol) was mixed with 2-morpholino-1-ethanol (0.1 mL) in pyridine (0.7 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase HPLC to give 2-morpholinoethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (24 mg, 0.048 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.2 mL) was added slowly. The precipitate was collected through filtration under nitrogen to give 2-morpholinoethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (24 mg, 0.045 mmol). 1H NMR (DMSO-d6) δ 1.88(m, 2H), 2.16(m, 2H), 3.55(m, 8H), 3.90(s, 3H), 4.03 (m, 4H), 4.49(m, 2H), 4.92(m, 1H), 7.07(m, 1H), 7.15(s, 1H), 7.65(bs, 2H), 7.84(s, 1H), 8.45(s, 1H), 8.75(s, 1H) 10.95(bs, 1H). LC/MS MH+=497.
Reaction SMILES: C(N[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)C=C.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(N3CCC(O)CC3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 4-hydroxypiperidine in place of allylamine, the title compound was synthesized.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M84) (0.34 g, 0.65 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (250 mg, 95%).