Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[CH:31][C:30]([F:48])=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[F:48][C:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14][C:13]=4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])=[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:45])([CH3:46])[CH2:40][C:41]=43)[C:34]2=[O:47])[CH:31]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
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: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
In a 10-mL microwave reaction vessel equipped with a magnetic stirring bar were placed 5-bromo-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one 205b (150 mg, 0.43 mmol), 10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 230a (248 mg, 0.50 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (2 mL). After the reaction mixture was stirred at 125° C. for 10 minutes, it was purified by flash chromatography (dichloromethane:methanol, 3:1) to give 36% (100 mg) of 261a as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:48][CH3:49])[C:13]([O:46][CH3:47])=[C:14]([CH:16]=[CH:17][C:18]([N:20]3[N:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]3[CH2:30][CH2:31][CH:32]=[C:33]3[CH2:37][CH2:36][N:35]([O:38]CC[Si](C)(C)C)[C:34]3=[O:45])=[O:19])[CH:15]=2)=[CH:4][N:3]=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:48][CH3:49])[C:13]([O:46][CH3:47])=[C:14]([CH:16]=[CH:17][C:18]([N:20]3[N:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]3[CH2:30][CH2:31][CH:32]=[C:33]3[CH2:37][CH2:36][N:35]([OH:38])[C:34]3=[O:45])=[O:19])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2N=Cc3ccccc3C2CCC=C2CCN(OCC[Si](C)(C)C)C2=O)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2N=Cc3ccccc3C2CCC=C2CCN(O)C2=O)c1OC
Temperature: 0 °C
Yield: 62.3 %

Procedure:
##STR22## A solution of 220 mg of [3-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-acryloyl}-1,2-dihydrophthalazin-1-yl]-propylidene]-1-(2-trimethylsilanyl-ethoxy)-pyrrolidin-2-one in 2 ml of trifluoroacetic acid is stirred for 20 hrs. and then concentrated. The residue is dissolved in 5 ml of methanol and treated with 57 mg of sodium bicarbonate in 2 ml of water. The reaction solution is concentrated, the residue is dissolved in 5 ml of water and cooled to 0° C. The crystals obtained are filtered off under suction. There are obtained 117 mg of white crystals. MS (ISP): 584.4 (M+H)+
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27](=[O:47])[N:28]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[C:20]3[CH:19]=2)[CH2:7]1)(=O)=O.[C-:48]#[N:49].[K+]>CS(C)=O>[C:48]([C@@H:6]1[CH2:7][N:8]([C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([N:28]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:38][C:39]4[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=4)=[O:47])=[C:20]3[CH:19]=2)[C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:10]1)#[N:49]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](OS(C)(=O)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C#N)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 90 °C

Procedure:
A mixture of (3R,5R)-1-(3-(bis(4-methoxybenzyl)carbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-5-(3-fluorophenyl)pyrrolidin-3-yl methanesulfonate (I-34) (0.17 g, 0.26 mmol), potassium cyanide (20 mg, 0.31 mmol) and DMSO (anhyd, 1 mL) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was partitioned in EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica chromatography eluting with an EtOAc/Hex gradient to yield 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-35). 1H NMR (400 MHz, CDCl3) δ 8.15-8.11 (m, 1 H), 7.80 (s, 1 H), 7.37-7.28 (m, 1 H), 7.22-7.15 (m, 5 H), 7.02-6.93 (m, 2 H), 6.93-6.86 (m, 5 H), 6.15 (dd, J=2.7, 7.7 Hz, 1H), 5.08 (dd, J=2.6, 7.9 Hz, 1 H), 4.72 (d, J=15.7 Hz, 2 H), 4.54 (d, J=15.8 Hz, 2 H), 4.20-4.14 (m, 1 H), 3.91-3.83 (m, 1 H), 3.82 (s, 6 H), 3.37-3.24 (m, 1 H), 2.82 (ddd, J=8.1, 10.1, 12.4 Hz, 1 H), 2.41 (ddd, J=2.8, 6.4, 12.4 Hz, 1 H). MS m/z 590.2 (M+1)+
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][O:8][CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH3:13]>C(=O)([O-])O.[Na+]>[CH3:7][O:8][CH:9]1[C:10]([CH3:14])=[CH:11][CH:12]([CH3:13])[CH:2]([C:1]([O:5][CH3:6])=[O:4])[O:3]1
Reactant: CC=CC(C)=COC
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1OC(OC)C(C)=CC1C
Temperature: -70 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 224 mg (2 mmole) of 1-methoxy-2-methyl-1,3-pentadiene. Reaction was then allowed to proceed at -30° C. for 1 hour, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 108 mg of desired optically active 2-methoxy-6-methoxycarbonyl-3,5-dimethyl-5,6-dihydropyran (yield: 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:31]([OH:32])=[CH:30][C:13]2[N:14]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1.[CH3:34]I>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:31]([O:32][CH3:34])=[CH:30][C:13]2[N:14]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1O
Reactant: CI
Product: COC(=O)CCCCCOc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OC

Procedure:
6-[[6-Hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-5-yl]oxy]hexanoic acid methyl ester was methylated with methyl iodide according to general operating instructions 8.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18](=[O:42])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:29][C:28]([F:31])([F:30])[CH2:27][C@@H:26]1[C:32]([O:34]CC1C=CC=CC=1)=[O:33])=[O:24])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:32]([C@H:26]1[CH2:27][C:28]([F:30])([F:31])[CH2:29][N:25]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([N:12]1[CH2:13][C:14]([F:16])([F:17])[CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:42])([OH:34])=[O:33]
Reactant: O=C(OCc1ccccc1)[C@H]1CC(F)(F)CN1C(=O)CCCCC(=O)N1CC(F)(F)C[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CC(F)(F)CN1C(=O)CCCCC(=O)N1CC(F)(F)C[C@@H]1C(=O)O
Yield: 97 %

Procedure:
0.59 g (0.001 mol) (R)-1-[6-[(R)-2-Benzyloxycarbonyl-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylic acid benzyl ester in 20 ml ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.12 g 5% palladium/carbon. After completion of the reaction the catalyst was filtered off, the solvent was distilled off, and the residue was dissolved in dichloromethane. Evaporation gave 0.4 g (97%) (R)-1-[6-[(R)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylic acid as a white foam. ISP-MS: 413 (MH)+; [α]D=+54.2° (c=1% in dimethylsulfoxide).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[C:5]([NH:7][C:8]1[CH:36]=[CH:35][C:11]([O:12][C:13]2[C:18]3[CH:19]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:20]4[C:21](=[O:23])[NH:22][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:18]3[CH:19]4[NH:27][CH2:26][CH2:25][CH2:24][N:20]4[C:21](=[O:23])[NH:22][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:35][CH:36]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCCN2C(=O)Nc3nccc(Oc4ccc(NC(=O)c5cccc(Br)c5)cc4)c3C21
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccnc3c2C2NCCCN2C(=O)N3)cc1)c1cccc(Br)c1

Procedure:
The title compound was synthesized by de-protection of 79 by HCl in MeOH. LC-MS (M+H=495, obsd.=495).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:34])[C:32]#[CH:33]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:33]=[C:32]([CH2:31][OH:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cc(CC4CCOCC4)cc(c1=O)c32
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide (0.185 g), PdCl2(PPh3)2 (0.012 g), and CuI (0.032 g) in 10 mL of diethylamine is added propargyl alcohol (0.02 mL). The reaction is stirred overnight. The mixture is concentrated and the resulting solid is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is recrystallized from CH2Cl2/Et2O to yield 0.09 g (56%) of N-(4-chlorobenzyl)-2-(hydroxymethyl)-6-oxo-8-(tetrahydro-2H-pyran-4-ylmethyl)-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a white solid, m.p. 196-198° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[Cl:27])[CH:18]=[N:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[CH2:29]([N:33]1C=CN=C1)CCC>[Cu]I.C1(C)C=CC=CC=1>[Cl:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[CH:18]=[N:17][N:16]=[C:15]1[C:9]1[S:8][C:7]2[C:6]3[CH:28]=[C:2]([C:29]#[N:33])[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: Fc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Reactant: CCCCn1ccnc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3Cl)cc1CCO2
Temperature: 160 °C
Yield: 30.3 %

Procedure:
A microwave tube was charged with 3-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-4-(2-chloro-4-fluoro-phenyl)-4H-[1,2,4]triazole (0.57 g; 1.2 mmol), K4-[Fe(CN)6] (101 mg; 0.24 mmol), CuI (23 mg; 0.12 mmol), 1-butylimidazole (0.32 ml; 2.4 mmol) and toluene (5 ml). The mixture was flushed with argon and heated in a microwave at 160° C. for 4 h. LCMS shows approx. 40% conversion so the same amount of K4[Fe(CN)6], CuI and 1-butylimidazole was added again and reaction mixture heated in a microwave at 170° C. for a further 4 h. The reaction mixture was partitioned between CH2Cl2 and water, the organic layer was dried (Na2SO4) and purified by ISCO then prep. LCMS to give 355 as a white solid (154 mg; 30%). δH (400 MHz, CDCl3) 3.19 (t, J=5.2, 2H), 4.36 (t, J=5.2, 2H), 7.08-7.11 (m, 2H), 7.23-7.32 (m, 1H), 7.43-7.52 (m, 3H), 7.81 (d, J=2.0, 1H), 8.23 (s, 1H). [M+H]+: 423
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[C@H:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)COCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Cl[CH2:40][C:41]([O:43]C)=[O:42]>>[NH2:27][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:40][C:41]([OH:43])=[O:42])[CH2:25][CH2:26]3)[CH:20]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cnn(C3CCN(CC(=O)O)CC3)c2)cc1-c1nc2ccccc2s1
Temperature: 40 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (211.0 mg, 0.5604 mmol), Cs2CO3 (730 mg, 2.24 mmol), and DMF (10 mL, 0.1 mol) at 0° C. was charged with methyl chloroacetate (0.0493 mL, 0.560 mmol) and then heated at 40° C. overnight. The solvent was removed in vacuo, and the material was dry-loaded onto silica gel for column chromatography, eluting with 2→5% MeOH/DCM. The fractions containing the pure ester were concentrated in vacuo and redissolved in conc. HCl. The material was transferred to a sealed tube, and heated overnight at 50° C. The HCl was removed using the corrosive pump to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.36 (br. s., 4H), 3.34 (d, J=11.4 Hz, 2H), 3.71 (d, J=9.1 Hz, 2H), 4.19 (br. s., 2H), 4.31-4.41 (m, 1H), 4.51 (br. s., 2H), 7.54-7.60 (m, 1H), 7.61-7.67 (m, 1H), 8.12-8.20 (m, 2H), 8.24 (d, J=7.1 Hz, 1H), 8.52 (d, J=1.3 Hz, 1H), 8.58-8.65 (m, 2H), 10.49 (br, s., 1H). MS (ES+): m/z=435.09 (100) [MH+]. HPLC: tR=2.24 min (ZQ2, polar—5 min).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=[CH:11][C:10]([S:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:9][C:8]=2[CH3:32])=[O:3].[OH-].[Na+]>C(O)C>[NH2:1][C:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=[CH:11][C:10]([S:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:9][C:8]=2[CH3:32])=[O:3]
Reactant: CCOC(=O)CCSc1cc(C)c2ncc(C(N)=O)c(Nc3ccc(F)c(OC)c3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(SCCC(=O)O)cc23)ccc1F
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A solution of Intermediate 52 (0.95 g) in ethanol (10 ml) was treated with 2M sodium hydroxide (10 ml) and the resulting solution was left standing at room temperature overnight. The solvent was evaporated in vacuo. The residue was dissolved in water and acidified with 2M hydrochloric acid to pH 4. The resulting precipitate was filtered off, washed with water and dried in vacuo to give the title compound as an orange solid (0.8 g).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH2:9]([CH2:13][C:14](=O)[CH3:15])[C:10]([CH3:12])=O.O>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=2)[C:10]([CH3:12])=[CH:9][CH:13]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(O)cc1

Procedure:
A mixture of 4.0 g of p-aminophenol and 4.0 g of acetonylacetone is heated under reflux in toluene for 3 hours using a Dean Stark water separator to yield 4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenol. Condensation with ethyl alpha-bromoisobutyrate in ethyl alcohol in the presence of potassium carbonate gives ethyl 2-[4-(2,5-di-methyl-1H-pyrrol-1-yl)-phenoxy]-2-methylpropanoate. Hydrolysis with 1.5 N sodium hydroxide solution yields 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenoxy]-2-methyl-propanoic acid, m.p. 178°-180°.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][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][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.B(F)(F)F.CCOCC.[CH:38](O)([CH3:40])[CH3:39]>>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][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][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:38]([CH3:40])[CH3:39])=[O:23])=[CH:25][CH:26]=1
Reactant: CC(C)O
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)OC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Temperature: 0 °C

Procedure:
A solution of 4.9 g of 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid and 3.4 ml. of boron trifluoride etherate in 20 ml. of isopropyl alcohol is stirred at reflux for 44 hours, allowed to cool, and poured into 120 ml. of ice cold 5% aqueous sodium carbonate solution. The white solid is collecetd by filtration and recrystallized from benzene-ethanol to yield the product as a white solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]([CH:9]=[N:10][C:11]1[N:16]=[C:15](O)[C:14]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:13][N:12]=1)[CH3:8]>C(OCC)C>[Cl:3][C:15]1[C:14]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:13][N:12]=[C:11]([N:10]=[CH:9][N:7]([CH3:8])[CH3:6])[N:16]=1
Reactant: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Yield: 87 %

Procedure:
POCl3 (1600 mL, 17.2M) was added gradually to mechanically stirred solid 2-[[(dimethylamino)methylene]amino]-4-hydroxy-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide (363 g, 1.20M). An exotherm was noted. The thick slurry was heated to reflux for 15 minutes. Upon cooling, ethyl ether was added and the precipitate filtered off. The resulting solid was suspended in water and treated with NaHCO3 (solid) to pH ~7.5. After extraction with methylene chloride, drying (MgSO4), and concentration, a yellow solid was obtained. Trituration with ethyl ether afforded a light-yellow compound. Upon drying at 40° C. in vacuo for 16 hours the desired compound (333 g, yield 87.0%, m.p. 178°-182° C.) was obtained.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)/[CH:5]=[CH:4]/[CH2:3][OH:2]
Reactant: COC(=O)/C=C/c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC/C=C/c1cccc(F)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of trans-3-fluorocinnamic acid methyl ester (69.61 g, 386 mmol) in dry dichloromethane (1 L) at −78° C. under nitrogen was added dropwise diisobutylaluminum hydride (neat, 172 mL, 965 mmol, 2.5 equiv.) via an addition funnel. After the addition was complete, the reaction mixture was allowed to warm to −30° C. and stirred for an additional 1 hour, then quenched with methanol (150 mL). Upon warming to room temperature, the reaction mixture was treated with saturated aqueous solution of sodium/potassium tartrate (300 mL) and stirred for 30 minutes. The organic layer was washed sequentially with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, brine, and dried (anhydrous sodium sulfate). The crude oil was purified by silica gel chromatography (0-50% ethyl acetate:hexane) to give 53.07 g (90%) of trans-3-fluorocinnamyl alcohol as a colorless oil. MS (ES) m/z 152.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH:12]2[C:17](=O)[CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]2)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:26][C:27]1[N:28]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH2:41])=[NH:40])=[CH:34][CH:33]=2)[CH:29]=[CH:30][N:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][C:10]1[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][C:17]=2[N:41]=[C:39]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH3:26])=[CH:33][CH:34]=2)[N:40]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: COc1cccc(CC(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)c1
Product: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(C(=O)OC(C)(C)C)CC3)c1
Yield: 62 %

Procedure:
tert-Butyl 4-(3-methoxybenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (373 mg, 62%) was synthesised from tert-butyl 3-(2-(3-methoxyphenyl)acetyl)-4-oxopiperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for synthesis of pyrimidines. MS (ES+) m/z 527.1 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+]>CO.O>[CH3:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]([OH:13])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 87 %

Procedure:
A solution of 0.10 mole (1 eq.) of α,α-dimethylphenylacetic acid methyl ester 2 in 150 mL of MeOH and 50 mL of water was added 1.02 mole (10.1 eq.) of KOH pellets. After stirring at room temperature for 3.5 days, the methanol was stripped off by rotary evaporation. To the residual liquid was added 100 mL of water and enough concentrated HCl to bring to ˜pH 3. The aqueous solution was extracted with Et2O (3×100 mL). The combined organic layers were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to give a white solid as α,α-dimethylphenylacetic acid 3 (87–89%).