Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[CH3:8][S:9][C:10](SC)=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>CC(O)C>[CH3:8][S:9][C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:7][C:5](=[O:6])[C:4]=1[C:2]#[N:3]
Reactant: N#CCC(N)=O
Reactant: CSC(=CC(=O)c1cccnc1)SC
Agent: [Na]
Solvent: CC(C)O
Product: CSc1cc(-c2cccnc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
Sodium (0.408 g, 17.75 mmol) was added to 2-propanol (100 mL) and the mixture was stirred at room temperature under nitrogen for 24 h. Additional sodium (0.25 g) was added. After 17 h at room temperature, the mixture was heated to 60° C. for 1 h to dissolve the rest of the Na metal and then cooled to room temperature. 2-Cyanoacetamide (2.15 g, 25.6 mmol) was added. After 30 min at room temperature, 3,3-bis(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one (5.7124 g, 25.4 mmol) was added. The mixture was stirred at room temperature for 30 min, at reflux for 2 h, and concentrated. The solid residue was dissolved in water (100 mL) and acidified with aqueous HCl (0.3 N, 100 mL) to give a suspension. The brown solid was collected by filtration and dried under vacuum to give 4-(methylthio)-2-oxo-6-(pyridin-3-yl)-1,2-dihydropyridine-3-carbonitrile (5.1267 g, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.68 (1H, br. s), 9.03 (1H, s), 8.74 (1H, dd, J=4.77, 1.51 Hz), 8.24 (1H, δ, J=8.03 Hz), 7.59 (1H, dd, J=8.03, 4.77 Hz), 6.70 (1H, br. s), 2.71 (3H, s); MS (ES+) m/z: 244 (M+H); LC retention time: 1.912 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=3)[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:32]4[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]4)=[CH:18][CH:17]=3)[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CCN1CCNCC1
Reactant: ClCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Solvent: C1COCCO1
Product: CCN1CCN(Cc2ccc(-c3cc4c(NCc5cccc(Cl)c5)ncnc4[nH]3)cc2)CC1
Temperature: 90 °C

Procedure:
(3-Chloro-benzyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (150 mg, 0.35 mmol) is suspended in 5 ml dioxane and treated with N-ethyl-piperazine. The mixture is heated to 90° C. for 7 h. The solvent is evaporated and the residue is purified by flash chromatography on 34 g of silica gel. The column is eluted using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:1.25 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. Fractions containing the title compound were pooled and concentrated on a rotary evaporator to give the title compound; m.p. 241-243° C.; MS-ES+: (M+H)+=461.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][C:38]([NH:29][CH:17]1[CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=2)[CH2:20][N:15]([C:13]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:14])[CH2:16]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)NCc3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 35 mg (0.26 mmol, 1.2 eq.) of benzyl isocyanate were reacted according to General Method 4. Yield: 74 mg (77% of theory)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]([CH3:18])([C:14]([OH:16])=[O:15])[CH3:17])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
A mixture of 32.62 g of 2,4-difluoronitrobenzene, 24.2 g of 2-aminoisobutyric acid, 15.2 g of potassium carbonate, 100 ml of acetonitrile, and 100 ml of water is heated at 80° for 2 days (until TLC shows little or no starting material). The reaction is then cooled and acetonitrile is removed under reduced pressure. The pH is adjusted to 5 with 4 N hydrochloric acid and the mixture is extracted with chloroform (3×300 ml). The organic layers are dried over sodium sulfate and concentrated. The material is used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:23]([CH2:25][CH2:26][C:27](OCCCC)=O)=[O:24]>>[CH2:1]([N:19]1[C:23](=[O:24])[CH2:25][CH2:26][CH:27]=[N:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCCNCCN
Reactant: CCCCOC(=O)CCC=O
Product: CCCCCCCCC=CCCCCCCCCN1CCN=CCCC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 310.1 g (1 mole) of N-(9-octadecenyl)ethylenediamine and 158.2 g (1 mole) of butyl 3-formylpropionate. At 150° C. and under a reduced pressure of 50 mmHg, 18 g of water and 74 g of butanol were distilled off to obtain 4-(9-octadecenyl)-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O-:17])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C(O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])Cc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccccc2)cc1
Yield: 404.9 %

Procedure:
To a suspension of (4′-phenoxyphenyl)acetate acid (0.456 g) in 4 ml of ethanol is added para-toluensulfonic acid (0.076 g) and the resulting mixture is refluxed for 2 hours. The solvent is evaporated off, the residue is dissolved in diethyl ether and the organic phase is washed with saturated aqueous solution of sodium hydrogencarbonate and then with brine. The organic phase is dried over sodium sulfate and concentrated to dryness to give 0.458 g of the product as a brown oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH2:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:54]4[CH2:55][CH2:56][CH:51]([CH2:50][O:49][CH2:47][CH3:48])[CH2:52][CH2:53]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOCC1CCN(C(=O)CC2CCN(C(=O)N3C(c4cnc(C(C)(C)C)cc4OCC)=N[C@@](C)(c4ccc(Cl)cc4)[C@@]3(C)c3ccc(Cl)cc3)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-(ethoxymethyl)-piperidine (VWR) to give the title product. LC-MS (ES+) 790 [(M+H)+].
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3ccccc3-c3ccccc3)c2O1
Yield: 88.9 %

Procedure:
Treatment of ((2R)-8-(biphenyl-2-yl)-6-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (1.30 g, 2.66 mmol) with sodium azide (1.04 g, 15.96 mmol) in DMSO (30 mL) according to the procedure described for Example 69, Step 9 provided 0.85 g (89%) of (2R)-2-(azidomethyl)-8-(biphenyl-2-yl)-6-fluorochroman as a pale yellow oil.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=4[F:37])=[O:28])[CH:25]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[F:38])C1C=CC=CC=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:38][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[OH:9])[N:17]=[CH:16][N:15]=[C:14]2[NH:20][C:21]1[CH:22]=[N:23][N:24]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=2[F:37])=[O:28])[CH:25]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:38][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[OH:9])[N:17]=[CH:16][N:15]=[C:14]2[NH:20][C:21]1[CH:22]=[N:23][N:24]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=2[F:37])=[O:28])[CH:25]=1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(OCc4ccccc4)c(F)cc23)cn1)Nc1cccc(F)c1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1cc(Nc2ncnc3cc(O)c(F)cc23)cn1)Nc1cccc(F)c1F

Procedure:
A solution of 2-(4-{[7-(benzyloxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide hydrochloride (1.90 g, 3.51 mmol) in trifluoroacetic acid (20 ml) was heated at 70° C. for 4 hours. The mixture was evaporated and the residue triturated with diethyl ether to give 2-{4-[(6-fluoro-7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}-N-(2,3-difluorophenyl)acetamide as the trifluoroacetic acid salt (1.89 g, 100% yield) as a pale yellow solid:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[C:27](Cl)[N:26]=1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:27]3[C:28]([Cl:32])=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[N:26]=3)[CH2:22][CH2:23]2)=[O:17])=[CH:12][CH:11]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)cc1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-methoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (972 mg) described in Preparation Example 165 and 2,3,5,6-tetrachloropyridine (990 mg), the title compound (1.25 g) was obtained.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[C:29]([CH3:30])[C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[C:48]3[S:47][N:46]=[N:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)O1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)[CH:19]=2)=[C:21]2[C:29]([CH3:30])=[C:28]([C:40]3[C:48]4[S:47][N:46]=[N:45][C:44]=4[CH:43]=[CH:42][CH:41]=3)[O:27][C:22]=12
Reactant: CC1(C)OB(c2cccc3nnsc23)OC1(C)C
Reactant: Cc1c(Cl)oc2c(N)ncc(-c3cnn([C@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)CC4)c3)c12
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: C1COCCO1
Product: Cc1c(-c2cccc3nnsc23)oc2c(N)ncc(-c3cnn([C@H]4CC[C@H](O)CC4)c3)c12

Procedure:
A solution of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chloro-3-methylfuro[2,3-c]pyridin-7-amine (20 mg, 0.043 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzothiadiazole (12.5 mg, 0.0477 mmol), and Pd(PPh3)4 (5.0 mg, 0.0043 mmol) in 1,4-dioxane (0.2 mL) and 1.0 M aqueous sodium carbonate (0.2 mL) was heated to 120° C. in a microwave for 60 min. The organic phase was separated, treated with 12 M aqueous HCl (0.071 mL) at 40° C. for 1 h, and then concentrated. Purification by ISCO chromatography (0 to 15% 7 N NH3/MeOH:DCM) followed by trituration from DCM:hexanes (˜5 mL, 1:1) and filtration afforded 5.3 mg (27%) of the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 8.83 (d, J=7.8 Hz, 1 H), 8.19 (d, J=6.8 Hz, 1 H), 7.90-8.03 (m, 2 H), 7.67 (s, 1 H), 7.58 (d, J=0.5 Hz, 1 H), 6.38 (s, 2 H), 4.67 (d, J=4.3 Hz, 1 H), 4.09-4.27 (m, 1 H), 3.42-3.60 (m, 1 H), 2.27 (s, 3 H), 2.06 (d, J=12.1 Hz, 2 H), 1.90-1.98 (m, 2 H), 1.77-1.90 (m, 2 H), 1.28-1.48 (m, 2 H); MS (ESI): 446.85, 448.96 [M+H]+; HPLC tR=2.51 min (ZQ3: polar—4 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][C:4]=2[F:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 140 °C
Yield: 62.3 %

Procedure:
A mixture of 77 (312 mg, 0.864 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (62%) of compound 78. 1H NMR (400 MHz, CDCl3): δ1.52 (s, 9H), 1.58 (m, 6H), 2.07 (br s, 2H), 2.25 (br s, 2H), 4.78 (s, 1H), 6.30 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.49 (d, J=16.0 Hz, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16](C1C=C(C=CC=1)C(Br)Br)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3.Cl>C(O)C.C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: BrC(Br)c1cccc(Oc2ccccc2)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
A process according to claim 1, wherein the mixture of m-phenoxybenzyl bromide (II) and m-phenoxybenzal bromide (X = bromine) is reacted with 1 to 2 molar equivalents of hexamethylenetetramine in hot aqueous ethanol or hot aqueous acetic acid and hydrolyzing the mixture with dilute hydrochloric acid to yield m-phenoxybenzaldehyde (I).
Reaction SMILES: CO.[H-].[Na+].[C:5]([O:12][CH3:13])(=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=1[CH2:25]Br>CCOCC>[CH3:10][O:9][C:7]([C:6]1([C:5]([O:12][CH3:13])=[O:11])[CH2:25][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][C:18]=2[N+:22]([O-:24])=[O:23])[CH2:15]1)=[O:8]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cccc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To a solution stirred under nitrogen at room temperature, to 5.0 mL methanol in 15.0 mL ether was added 60% sodium hydride (0.84 g, 0.021 mol) in small portions. After the addition was complete, the nearly clear and colorless solution was stirred for 5 minutes. To it was then added 1.3 g dimethyl malonate, giving a slightly cloudy colorless solution. To this was rapidly added a suspension of 3.1 g 1,2-bis(bromomethyl)3-nitrobenzene, which immediate gave a precipitate suspended in a dark green solution. This was removed by filtation and the filtrate was concentrated. The residue was purified on silica (20%-100% CH2Cl2 in hexanes) to give 1.93 g off-white solid (67%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>ClCCl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Nc1ncc(CO)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 5643.2 %

Procedure:
A solution of methyl 6-amino-5-iodonicotinate (335 mg, 1.205 mmol) in dichloromethane (18 mL) was added DIBAL (1.5 M in toluene, 1.61 mL, 2.41 mmol) via syringe dropwise at 0° C. The reaction was monitored by LC_MS, and added more DIBAL (0.8 mL, 1.2 mmol) to drive the reaction to complete. The reaction was quenched with addition of MeOH (1 mL) dropwise at 0° C., stirred at rt for 2 h and filtered through a CELITE® pad, rinsed with ethyl acetate and dichloromethane. The organic layers were combined and concentrated onto SiO2 which was purified by a flash column using 50%, 80% and 100% ethyl acetate in heptane as an eluent to give the product (204 mg, 68 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH3:22]>CC(O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH2:22])=[N:3][CH:4]=1
Reactant: N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(N)ncc1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
In a sealed tube, a mixture of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (100 mg, 0.289 mmol) and ammonia (2 M in 2-propanol, 1.44 ml, 2.89 mmol) in 2-propanol (1.5 ml) was stirred at 80° C. for 2 days, then ammonia (2 M in 2-propanol, 1.44 ml, 2.89 mmol) was added and the reaction mixture was stirred at 80° C. for 7 days. The reaction mixture was cooled to room temperature and evaporated; the crude mixture was then diluted with EtOAc and washed with water; the organic phase was then dried over Na2SO4, filtered and evaporated to give the title compound as a yellow resin. (UPLC-MS 1) tR 0.83 min; ESI-MS 327.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38](Cl)=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(Cl)Cc1ccccc1Cl
Product: O=C(Cc1ccccc1Cl)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-chlorophenyl-acetyl chloride according to the procedure of Example 61. MS (ES) m/z 542.8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:19][C:20]1([CH3:36])[O:25][CH:24]([C:26]([NH:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:27])[C:23]([CH3:35])([CH3:34])[CH2:22][O:21]1>>[CH3:19][C:20]1([CH3:36])[O:25][CH:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:32])=[O:27])[C:23]([CH3:35])([CH3:34])[CH2:22][O:21]1
Reactant: CCCCCCCCCCCC(=O)NCCCO
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 64.1 %

Procedure:
N-(3-Hydroxypropyl)dodecanamide (2.57 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 3.19 g of the title compound (yield: 64%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.[OH-].[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
To a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (46 mg, 0.137 mmol) in DCM (1 ml) was added DIPEA (0.119 ml, 0.684 mmol) and cyclopropyl carbonyl chloride (29 mg, 0.274 mmol). The reaction was stirred at room temperature for 1 hour, then 2M sodium hydroxide solution (2 ml) was added and the reaction stirred at room temperature for a further 1 hour. The organic layer was collected by passing through a hydrophobic frit. The aqueous layer was washed several times with DCM. The organic extracts were combined and solvent removed by blow down. The residue was dissolved in methanol (2 ml) and 4M HCl in 1,4-dioxane added (2 ml). The reaction was stirred at room temperature for 1 hour. The solvent was removed by blow down and the residue purified by mass directed preparative HPLC (method B). The residue was freeze dried to give the title compound as a pale brown solid (9 mg).