Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)=CC.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.P([O-])([O-])([O-])=O>CC(C)=O>[CH3:23][C@:22]12[CH2:21][CH2:20][C@H:19]3[C@@H:9]([CH2:10][CH:11]=[C:12]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:14](=[O:24])[CH2:13]4)[C@@H:8]1[CH2:7][CH:6]=[CH:5]2
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC=C3CC(=O)CC[C@]3(C)[C@H]1CC2
Reaction time: 0.08 h
Yield: 104.8 %

Procedure:
This synthesis is depicted in FIG. 179. To a solution of alcohol 8 (545 mg, 2.0 mmol) in acetone (100 ml) at 0° C. under N2 was added rapidly Jones reagent (i, 1.5 ml, ca. 4 mmol). After 5 min., the mixture was poured into a dilute phosphate buffer (pH 7.2, 1200 ml) and extracted with ether. The extracts were washed with sat. aq. NaCl solution, dried (Na2SO4) and evaporated to give mainly Androsta-5,16-dien-3-one as an oil (567 mg). The crude product was dissolved in THF (7 ml) and reduced with lithium tris (1,2-dimethylpropyl) hydridoborate (c) at 0.55° as described for the preparation of 2. The crude product (530 mg) was chromatographed on silica gel (100 g) with CH2Cl2/ethyl acetate 4:1 to give 280 mg (51%) of pure a-alcohol 7 (eluted first) and 13 mg of 5 starting alcohol 8. A small sample of 7 was recrystallized from acetone/water at RT. M.p. 1380, [B]D −77.5° (c=1.2. -IR. (CDCl3): 3580m, 3430m, 1665w, 1590w, -1H-NMR. (360 MHz): 0.80 (s, 3 H); 1.06 (s, 3 H); 4.02 (m, w½8, 1 H); 5.44 (m, 1 H); 5.72 (m, 1 H); 5.86 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:33].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2COc1cccc(C(F)(F)F)c1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2COc1cccc(C(F)(F)F)c1

Procedure:
According to the general procedure (GP12), chlorination of 3-ethyl-1-iodo-8-(3-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.272 g; 2.307 mmol), and purification by FC (DCM/MeOH=60/1) gave the expected product 1-chloro-3-ethyl-8-(3-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (0.403 g; 38%). LC-MS: tR=1.03 min.; [M+H]+=460.37 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([N:19]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:13]1([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCN(c2ccccc2)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(c2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 6.9 g (0.037 mole) of 4-nitrobenzoyl chloride in 30 ml. of chloroform was added dropwise at room temperature to a stirred mixture of 6 g. (0.037 mole) of 1-phenyl-3-aminopyrrolidine and 10 g. of potassium carbonate in 30 ml. of water and 30 ml. of chloroform. The mixture was stirred 30 minutes, the chloroform layer separated, dried over magnesium sulfate and evaporated. Recrystallization of the crude solid residue from alcohol-water gave 10.6 g. (92%) of an orange solid which melted at 153-155° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH2:44][C:45]#[N:46])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: N#CCBr
Reactant: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
A solution of (R)-tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.206 mmol) in DMF (2 ml) was added potassium carbonate (85 mg) and 2-bromoacetonitrile (44 μl, 0.618 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (55 mg). 1H NMR (500 MHz, CDCl3): 7.35 (s, 1H), 7.20-7.32 (m, 9H), 4.98 (q, 1H), 4.87 (dd, 2H), 2.44-2.49 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.75 (d, 3H), 1.24-1.36 (br, 9H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:24])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.C1([O:57][C:58](=O)[NH:59][C:60]2[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=2)C=CC=CC=1>CN1C(=O)CCC1>[CH2:26]([O:25][C@H:23]([CH3:24])[C:22]([NH:21][C@H:19]1[CH2:20][C@@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:58]([NH:59][C:60]4[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=4)=[O:57])[CH2:3]2)=[N:8][C:9]=3[NH:36][CH2:37][CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C@H:17]([OH:35])[C@@H:18]1[OH:34])=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution comprising (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (1 equivalent) and pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB) (1 equivalent) in NMP is stirred at 100° C. for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by column chromatography/crystallisation.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O>CO>[NH2:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: COC(=O)C1(CN)CC12CCCC2
Agent: [Li]O
Solvent: O
Solvent: CO
Product: NCC1(C(=O)O)CC12CCCC2
Yield: 38.8 %

Procedure:
To a solution of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.40 g, 18.6 mmol) was added methanol (75 mL) and LiOH—H2O (1.55 g, 37.1 mmol). The mixture was heated to reflux under nitrogen for 48 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in water (50 mL). With ice bath cooling, concentrated HCl (˜2.5 mL) was added until the pH was adjusted to 6. A white precipitate was isolated by filtration and dried under vacuum to yield 1.22 g (39%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid as an off-white solid: mp 231–235° C. (decomposition); 1H NMR (300 MHz, D2O) δ 0.78 (d, J=4.7 Hz, 1H), 1.32 (d, J=4.7 Hz, 1H), 1.40 (m, 1H), 1.54–1.77 (m, 7H), 2.86 (d, J=13.2 Hz, 1H), 3.43 (d, J=13.2 Hz, 1H); MS (APCI) m/z 170 [M+H]+. Anal. Calcd. For C9H15NO2 −1.1H2O: C, 57.18; H, 9.17; N, 7.41. Found: C, 57.38; H, 8.82; N, 7.09.
Reaction SMILES: [C:1]([NH:4][CH:5](P(OC)(OC)=O)[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].C1CCN2C(=NCCC2)CC1.[O:27]1[CH:31]=[CH:30][C:29](C=O)=[C:28]1C=O>C(Cl)(Cl)Cl>[O:27]1[C:31]2[CH:30]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[N:4]=[CH:1][C:2]=2[CH:29]=[CH:28]1
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Reactant: O=Cc1ccoc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2occc2cn1
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
Methyl (acetylamino)(dimethoxyphosphoryl)acetate (2.34 g, 9.8 mmol) is dissolved in CHCl3 (40 mL), treated with DBU (1.46 mL, 9.8 mmol), stirred for 5 min then added dropwise to a 0° C. solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHCl3 (80 mL). The mixture is stirred for 2.5 h as the cooling bath expires then 5.5 h at RT and finally 24 h at 50° C. The mixture is concentrated in vacuo to a yellow oily-solid (6.66 g). The crude material is chromatographed over a standard 100 g slurry-packed silica gel, eluting with 65% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 1.30 g (82%) of methyl furo[3,2-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 177 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:18].[CH3:19][Mg]Br.[NH4+].[Cl-].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH3:19])[OH:18]
Reactant: C[Mg]Br
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A suspension of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (35 g, 107 mmol) in dry THF (210 mL) under nitrogen atmosphere was cooled to 0° C. and a solution of methylmagnesium bromide (3.0M solution in diethyl ether; 107 mL, 320 mmol) in dry THF (70 mL) was added over 10 minutes via an addition funnel. After complete addition a saturated aqueous solution of NH4Cl (125 mL) was added slowly to the stirring reaction mixture, keeping the internal temperature below 30° C. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate before concentrating under reduced pressure to afford 7-bromo-3-chloro-1-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (34.33 g, 100 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:14])[CH3:13]>C(O)CCC>[CH2:12]([NH:14][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2)[CH3:13]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCN
Solvent: CCCCO
Product: CCNc1nc(Cl)nc2nc[nH]c12
Temperature: 84 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2,6-dichloropurine (2 g, 10.6 mmol) in n-butanol (3 ml), is added ethylamine (2M in THF)(15 ml). The solution is stirred at 84° C. for 2.5 hours and then cooled to ambient and stirred for a further 2 hours. The resulting precipitate is isolated by filtration, washed with n-butanol, methanol and ethyl acetate. The solid is dried at 70° C., under vacuum, for 16 hours to give 6-ethylamino-2-chloropurine; ES+ (M+1)197.5,198.2; mp 237-239° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride (260 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2].O=[C:24]([CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:25]([OH:27])=[O:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:24]([C:25]([OH:27])=[O:26])[CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(=O)CCCN1CCCCC1
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Product: O=C(O)C(CCCN1CCCCC1)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 13, 7-nitro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 2-oxo-5-piperidinopentanoic acid at room temperature to give 7-nitro-2-[(1-carboxy-4-piperidinobutylidene)-hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)=[O:17])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[CH3:30][NH2:31]>CO>[OH:11][CH:10]([CH2:12][NH:31][CH3:30])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=2)=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: CN
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Solvent: CO
Product: CNCC(O)COc1c(C)cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc1C

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (33 mg, 82 μmol) and methylamine (0.082 mL, 2 M solution in THF) in methanol (1 mL) is stirred at 65° C. for 4 h and at rt for 18 h. The solvent is removed in vacuo and the residue is purified by prep. HPLC to give 3-[4-(2-hydroxy-3-methylamino-propoxy)-3,5-dimethyl-phenyl]-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (4 mg) as a colourless resin; LC-MS: tR=0.88 min, [M+1]+=438.25, 1H NMR (as formate salt) (CDCl3): δ 8.56 (s, 1H), 7.60 (s, 1H), 7.45-7.30 (m, 5H), 6.85 (m, 2H), 4.60 (s br, 2H), 4.37-4.30 (m, 1H), 3.81-3.20 (m, 2H), 3.18-3.10 (m, 4H), 2.96-2.88 (m, 2H), 2.70 (s, 3H), 2.51 (s, 3H), 2.20 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:17][C:18]2[CH:33]=[CH:32][C:21]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(N)=O)[CH:24]=3)=[C:20]([F:34])[CH:19]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35].[NH2:36]C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1>>[ClH:35].[ClH:35].[NH2:36][C:25]1[CH:24]=[C:23]([O:22][C:21]2[CH:32]=[CH:33][C:18]([NH:17][C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])=[CH:19][C:20]=2[F:34])[CH:28]=[CH:27][N:26]=1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)NCc3ccccc3)cc2F)ccn1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Product: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)NCc3ccccc3)cc2F)ccn1
Yield: 69 %

Procedure:
4-(4-(3-(Benzylcarbamoyl)pyridin-2-ylamino)-2-fluorophenoxy)picolinamide (0.068 g, 0.15 mmol) was converted to the title compound (0.051 g, 69%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 9.44 (t, 1H, J=5.7 Hz), 8.10-8.35 (m, 3H), 7.91 (d, 1H, J=7.2 Hz), 7.82 (br s, 2H), 7.15-7.42 (m, 7H), 6.90-6.94 (m, 1H), 6.65 (dd, 1H, J=7.2, 2.5 Hz), 6.12 (d, 1H, J=2.5 Hz), 4.45 (d, 2H, J=5.8 Hz); HRMS(ESI+), 430.1679 (M+H)+ calc, 430.1683 (M+H)+ found.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:25]2[CH:34]=[C:33]([C:35](O)=[O:36])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:25]2[CH:34]=[C:33]([C:35]([NH:1][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]5[CH2:20][CH2:19]5)=[O:15])=[CH:10][CH:9]=4)[C:5]([CH3:21])=[CH:4][CH:3]=3)=[O:36])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cc(C2CC2)nc2ccccc12
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(C3CC3)nc3ccccc23)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and 2-cyclopropylquinoline-4-carboxylic acid (85.3 mg, 0.4 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 30 min at room temperature. Carbodiimde resin (442 mg, 0.5 mmol) was added and shaking continued for 18 h. The solution was filtered off, the resin washed with THF and methanol and the combined filtrate and washings reduced to dryness under vacuum. The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M) and aqueous sodium hydrogen carbonate. The solvent was evaporated from the organic fraction under vacuum to give 2-cyclopropyl-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)quinoline-4-carboxamide. NMR; δH [2H6]—DMSO 10.74,(1H, s), 8.62,(1H, t), 8.04,(1H, d), 7.94-7.90,(3H, m), 7.74-7.70,(3H, m), 7.62,(1H, s), 7.53,(1H, m), 7.45,(2H, d), 7.33,(1H, d), 3.16,(2H, t), 2.37,(1H, m), 2.22,(3H, s), 1.15-1.10,(5H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.61 min, MH+476.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:16])=[N:4][C:5]2[CH:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][C:10]=2[N:11]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>O1CCOCC1>[Cl:16][C:3]1[C:2]([NH:20][CH2:17][C:18]#[CH:19])=[N:11][C:10]2[CH:9]=[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: C#CCN
Reactant: Clc1nc2cc3ccccc3cc2nc1Cl
Solvent: C1COCCO1
Product: C#CCNc1nc2cc3ccccc3cc2nc1Cl
Yield: 72.7 %

Procedure:
A mixture of 2,3-dichlorobenzo[g]quinoxaline (0.634 g, 2.55 mmol), propargylamine (0.21 ml, 3.05 mmol) and TEA (0.53 mL, 3.83 mmol) in 15 mL of dioxane was heated to reflux for 4.5 hours. After evaporating the resulting mixture under vacuum, the crude product was chromatographed (CH2Cl2) to afford the title compound as a yellow solid (0.496 g, 73%); mp 169-172° C.; IR (KBr, cm−1) 3412, 3283, 3235, 1570, 1508, 1335; −1H NMR (DMSO) δ 8.44 (s, 1H), 8.26 (s,1H), 8.16-8.06 (m, 3H), 7.58-7.54 (m, 1H), 7.51-7.48 (m, 1H), 4.28 (dd, J=6.1, 2.5, 2H), 3.12 (t, J=2.5, 1H); LC/MS 97.8% (220 nm), m/z (M+H+) 268.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:32][CH:31]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Nc1ccc(F)c(Cl)c1
Yield: 78 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-N-(3-chloro-4-fluorophenyl)-5-methylpyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 78% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 440.4 [M+H]+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([N:47]=[N+:48]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N+:47]=[N-:48])(=[O:17])=[O:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C(Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(=O)c3ccccc3)cc2)cc1)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: [N-]=[N+]=C(S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1)S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 37 %

Procedure:
The bis(4-benzoyloxyphenylsulfonyl)methane in Synthesis Example 6, 10 g (0.019 mol), was dispersed in 200 g of dichloromethane. To the dispersion was added 5.6 g (0.029 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring under ice cooling, 4.0 g (0.026 mol) of DBU was added to the dispersion, and after 5 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 15 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 40 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 37%) of fine yellow crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.FC(F)(F)[C:28]1[NH:29]C2C(C=1)=CC(CN)=CC=2>>[C:2]([C:3]1[N:29]=[CH:28][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15]3)=[O:9])=[CH:5][CH:4]=1)#[N:7]
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1cccc(Br)n1
Agent: Cl
Product: N#Cc1ccc(C(=O)NCc2ccc3[nH]c(C(F)(F)F)cc3c2)cn1

Procedure:
The title compound was prepared by a similar procedure to that described for Compound 3 using the appropriate carboxylic acid with 2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>O>[CH3:16][O:15][C:13]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])=[O:14]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(C(=O)O)cc1F
Temperature: -20 °C
Reaction time: 4 h

Procedure:
4-methoxycarbonyloxy-3-fluorobenzoic acid (VI) was synthesized from 3-fluoro-4-hydroxybenzoic acid (V) by reaction of the latter with methyl chloroformate. NaOH (90 mmol) and 3-fluoro-4-hydroxybenzoic acid (30 mmol) were dissolved in water (80 ml) and cooled to -20° C. Methyl chloroformate (45 mmol) was added dropwise to the mixture. The mixture was then stirred with a magnetic stir bar at 5° C. for four hours and left overnight in the refrigerator. The mixture was then acidified to pH 5 to precipitate 4-methoxycarbonyloxy-3-fluorobenzoic acid. The precipitates were filtered and crystallized from acetonitrile to afford the clean product, 4-methoxycarbonyloxy -3-fluorobenzoic acid (VI), in a 77% yield.