Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:6]=1)C.[OH-].[Na+]>CO>[CH:15]([NH:14][C:12](=[O:13])[NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:4]([OH:18])=[O:3])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1ccnc(NC(=O)NC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(3-Isopropyl-ureido)-isonicotinic acid ethyl ester (130 mg, 0.52 mmol) in MeOH (5 ml) is added 2 M NaOH (2.5 ml) and the resulting solution is stirred for 1.5 hours at room temperature. The solvent is removed in vacuo and sat. aq. NH4Cl solution is added. The pH of the aqueous phase is adjusted to 1 using 1 M HCl and the product extracted into EtOAc, dried (MgSO4) the solvent removed in vacuo to afford 2-(3-Isopropyl-ureido)-isonicotinic acid as a white solid; [M+H]+ 224
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH:17]([F:19])[F:18])[C:3]=1[C:20]#[N:21].[CH3:22][C@H:23]1[O:28][C@@H:27]([CH3:29])[CH2:26][NH:25][CH2:24]1.[F-].[K+].O>CS(C)=O>[F:18][CH:17]([F:19])[C:4]1[C:3]([C:20]#[N:21])=[C:2]([N:25]2[CH2:24][C@H:23]([CH3:22])[O:28][C@H:27]([CH3:29])[CH2:26]2)[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)F)c(C#N)c2Cl)nc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2c(C#N)c(C(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)C[C@H](C)O1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
5-Chloro-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile (1.24 g, 3.7 mmol) and 2,6-cis-dimethylmorpholine (0.86 g, 7.4 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (13 ml) and potassium fluoride (0.43 g, 7.4 mmol) was added to the clear solution. The resulting mixture was stirred at 20° for a period of 2 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (30 ml). The organic extract was dried over sodium sulfate and concentrated with a rotary evaporator. The desired product (1.3 g, 85%) was isolated by triturating the residue with ether (10 ml) containing 3 drops of methanol, stirring the suspension overnight, filtering, and drying under high vacuum. MS: 412.5, r.t.: 2.2, 1HNMR: (in d6-DMSO solvent) 9.02(1H, d, J=2.4), 8.52(1H, dd, J=8.8, 2.8), 7.98(1H, d, J=8.8), 7.12(1H, t, J=52.8), 3.68(2H, m), 3.36(3H, s), 3.28(2H, m), 2.80(2H, m), 0.99 (6H, d, J=6.4) ppm, 13C-NMR: (in d6-DMSO solvent) 155.9, 154.2, 148.2, 139.6, 119.2, 113.2, 113.1, 112.0, 109.9, 79.0, 71.6, 55.9, 44.3, 18.9 ppm.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:29][CH2:30][CH3:31])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:29][CH2:30][CH3:31])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: CCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 84.2 %

Procedure:
Methyl 2-[2-(4-{2-[(2,4-difluorobenzyl)(propyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (0.22 g, 0.442 mmol) was dissolved in a mixture of THF/water (1/1, 4 ml). Lithium hydroxide (0.021 g, 0.884 nmol) was added. The reaction was performed in an single node microwave oven (14 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The waterphase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.180 g of 2-[2-(4-{2-[(2,4-difluorobenzyl)(propyl)-amino]-2-oxoethoxy}phenyl)ethoxy]benzoic acid (yield 84.2%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: O=Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A solution of 12.5 ml (0.15 mol) of methyl propiolate in 150 ml of tetrahydrofuran was treated at -78° under argon with 100 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9.8 g (80 mmol) of 4-hydroxybenzaldehyde in 50 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 200 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were dried in sequence with saturated sodium sulphate and concentrated The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(4-hydroxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.I[CH2:19][CH:20]([CH3:22])[CH3:21]>>[CH3:15][O:14][C:12]([C:10]1[CH:11]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=[C:5]2[C:9]=1[N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:7]=[CH:6]2)=[O:13]
Reactant: CC(C)CI
Reactant: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Product: COC(=O)c1cc(C(F)(F)F)cc2cnn(CC(C)C)c12
Yield: 39 %

Procedure:
Compound 12 was prepared following general method 1, using compound 4 as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 39%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (319 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a pale pink foam (460 mg, 83%).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][CH:8]=[CH2:9])C=C.CN1C(C2CCCC=C[O:26]2)=C([N+]([O-])=O)C=N1.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH:8]12[O:26][CH:7]1[CH2:6][CH:5]([C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[O:4][CH2:1][CH2:9]2
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCCC=CO1
Reactant: C=CCCC(OCC=C)c1c([N+](=O)[O-])cnn1C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CC2OC2CCO1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
5-(1-Allyloxypent-4-enyl)-1-methyl-4-nitro-pyrazole (7.08 g, 28.2 mmol) was dissolved in DCM (910 mL) and the mixture degassed for 30 min before Grubbs 2nd generation catalyst (1.19 g, 1.41 mmol) was added. The reaction mixture was heated at 40° C. for 18 hr and concentrated under reduced pressure. Purification via silica gel column chromatography (0-10% EtOAc/isohexane) followed by reverse-phase preparative HPLC gave a mixture of isomers of 1-methyl-4-nitro-5-(tetrahydrooxepin-2-yl)pyrazole (66/34) as a clear oil (2.3 g). To a solution of this oil (2.3 g, 10.31 mmol) in DCM (50 mL) was added m-CPBA (70-75%, 3.56 g, 14.40 mmol) and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×50 mL), water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-(4,8-dioxabicyclo[5.1.0]octan-5-yl)-1-methyl-4-nitro-pyrazole as a colourless solid (1.0 g, 14% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.51-5.44 (m, 1H), 4.02 (s, 3H), 3.93 (dt, J=12.7, 3.4 Hz, 1H), 3.62-3.53 (m, 1H), 3.35-3.27 (m, 2H), 2.58-2.51 (m, 1H), 2.41-2.25 (m, 3H).
Reaction SMILES: B(F)(F)F.[BH4-].[Na+].[Cl:7][C:8]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13](=O)[C:12]1([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C:12]1([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C1(C)C(=O)N(C)CCN1Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CN(C)CCN1Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
4.4 ml of freshly distilled boron trifluoride are added dropwise, while cold, to 1.1 g of dry sodium borohydride suspended in 35 ml of freshly distilled tetrahydrofuran. The reaction mixture is stirred at 0° C. for 2 hours and then 3.5 g (0.01 mol) of the compound obtained in Step g in 100 ml of tetrahydrofuran are added. The mixture is then heated under reflux for one hour and then 50 ml of a 2N hydrochloric acid solution are added while cold. The mixture is neutralised with sodium hydroxide and then extracted with ether. Customary treatment of the organic phase yields a crude product which is purified over a silica gel column (eluant: trichloromethane). 1 g of the pure desired product is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:48][CH:49]1[CH2:56][C@H:55]2[C@H:51]([CH2:52][NH:53][C@@H:54]2[CH2:57][NH:58][C:59](=[O:64])[C:60]([F:63])([F:62])[F:61])[CH2:50]1>CN(C=O)C.CC(=O)OCC.CC(=O)OCC.CCCCCCC.O>[F:63][C:60]([F:61])([F:62])[C:59]([NH:58][CH2:57][C@H:54]1[N:53]([C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:52][C@H:51]2[C@@H:55]1[CH2:56][CH:49]([CH3:48])[CH2:50]2)=[O:64]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)C(F)(F)F)[C@H]2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1
Reaction time: 16 h

Procedure:
A solution of 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid (1 g, 1 eq), DIPEA (3.7 mL, eq) and TBTU (1.4 g, 1 eq) in dry DMF (15 mL) was stirred at RT for 15 min. Then was added a solution of N-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-2,2,2-trifluoro-acetamide (1.082 g, 1 eq) in dry DMF (15 mL). The resulting reaction mixture was stirred for 16 h, poured into water and diluted with EA. The org. phase was washed with a sat. aq. NaHCO3 solution, brine, dried over anh. MgSO4, filtered and concentrated to yield a crude yellow solid. FC (EA/n-heptane: 3/7 to 7/3) gave the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[C:3](N)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H+].[B-](F)(F)(F)[F:13].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[F:13][C:3]1[C:2]([I:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: COc1ccnc(N)c1I
Reactant: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: COc1ccnc(F)c1I
Temperature: -20 °C

Procedure:
To a cold (−20° C.), stirred suspension of the 3-iodo-4-methoxypyridin-2-amine (2.5 g, 10 mmol) in HBF4 (70 mL, 470 mmol) was added an aqueous solution of NaNO2 (1.67 M, 6 mL, 10 mmol) over 20 min. The reaction turned green and then brown in color. The mixture was stirred at 0° C. for 3 h. The reaction was then carefully poured into a cold (0° C.) saturated solution of Na2CO3 (50 g) in H2O (100 mL). The layer was then extracted with EtOAc (×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica gel (elution with 5:1 to 2:1 hexanes:ethyl acetate) to yield 2-fluoro-3-iodo-4-methoxypyridine as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(F)cc2)c(N)n1
Product: CC(=O)N1CCC(Nc2ncc(C(=O)c3ccc(F)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-fluoro-phenyl)-methanone (Example 366) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-fluoro-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 358.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+]>O1CCCC1CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methyl trans-4-{[(2-{[(5-chloropyridin-2-yl)-amino]carbonyl}benzofuran-3-yl)amino]carbonyl}cyclohexane-carboxylate (300 mg) obtained in Example 8(1) is suspended in tetrahydrofuran-methanol (4:1) (10 ml) and thereto is added 10% aqueous sodium hydroxide solution (1 ml). The mixture is warmed to room temperature and stirred for 17 hours. The reaction solution is concentrated under reduced pressure, thereto added ice-water, and the mixture is acidified by addition of 10% hydrochloric acid. The precipitates are collected by filtration, washed with water, and dried to give trans-4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}benzofuran-3-yl)amino]carbonyl}-cyclohexanecarboxylic acid (270 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[PH2]([O-])=O.[Na+].O.O[CH2:23][CH:24]([CH2:26]O)O>S(=O)(=O)(O)O>[CH:23]1[C:6]2=[C:7]3[C:12]([C:13]([C:14]4[C:5]2=[CH:4][CH:3]=[CH:2][CH:1]=4)=[O:15])=[CH:11][CH:10]=[CH:9][C:8]3=[CH:26][CH:24]=1
Reactant: OCC(O)CO
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2-c2cccc3cccc1c23
Temperature: 120 °C
Reaction time: 3 h

Procedure:
208 g of anthraquinone are dissolved in 1,000 g of concentrated sulphuric acid at 80°-110°. 96 g of sodium hypophosphite, dissolved in 240 g of glycerol, are added to this solution in a manner such that a temperature of 100° C. can be maintained. The mixture is then heated to 120° C. and kept at this temperature for 3 hours. The melt is then poured into 3 l of water and the product which has precipitated is filtered off. It is washed with hot water until the runnings are almost colourless, the filter cake is then suspended in 1.5 l of water and the suspension is rendered weakly alkaline and boiled up. After renewed filtration of the product, washing with hot water and drying at 100° C., 200-225 g of 92-97% pure benzanthrone≈80-93% of theory result.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](Cl)(=[O:8])[CH3:7].C1COCC1.O.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:27]1[CH:32]([NH:33][C:34]2[C:41]([F:42])=[CH:40][C:37]([C:38]#[N:39])=[C:36]([NH:43][C:44]3[CH:45]=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=3)[N:35]=2)[CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C>[C:6]([N:29]1[CH2:30][CH2:31][CH:32]([NH:33][C:34]2[C:41]([F:42])=[CH:40][C:37]([C:38]#[N:39])=[C:36]([NH:43][C:44]3[CH:45]=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=3)[N:35]=2)[CH:27]([N:18]2[C:19](=[O:26])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:16])[CH2:28]1)(=[O:8])[CH3:7]
Reactant: Cc1cncc(Nc2nc(NC3CCNCC3N3C(=O)c4ccccc4C3=O)c(F)cc2C#N)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(Nc2nc(Nc3cncc(C)c3)c(C#N)cc2F)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydrogen carbonate (13 mg) and acetyl chloride (0.005 ml) were added to a THF/water (0.5 ml/0.5 ml) solution containing 6-((3-(1,3-dioxoisoindolin-2-yl)piperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile (15 mg) obtained in the 2nd step under ice cooling, followed, by stirring at room temperature for 0.5 hours. Ethyl acetate was added to the reaction solution. The obtained organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure. Yellow oily matter of 6-((1-acetyl-3-(1,3-dioxoisoindolin-2-yl)piperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile (12 mg) was thus obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25]>C(O)(C)C.Cl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=[N:22][NH:23][C:24](=[NH:25])[NH2:26])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)NN
Reactant: O=Cc1c(-c2ccccc2)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)O
Product: N=C(N)NN=Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 80 °C
Yield: 20 %

Procedure:
A mixture of DMF (11.0 mL, 142 mmol) and phosphorous oxychloride (3.63 mL, 39 mmol) is stirred at 0° C. for 1 h, a 0.2 mL portion is pipetted into a solution of 2-phenylindole (96 mg, 0.5 mmol) in DMF at 5° C. This reaction mixture is stirred at 5°-10° C. for 1 h, quenched with water, stored at −200 for 16 h and filtered. The filtercake is washed with water and dried in vacuo to afford the 2-phenylindole-3-carboxaldehyde intermediate. A suspension of the thus-obtained 2-phenylindole-3-carboxaldehyde (44.2 mg, 0.2 mmol) in isopropanol and concentrated HCl (50 μL) is treated with aminoguanidine bicarbonate (27 mg, 0.2 mmol), heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 28 mg (20% yield), identified by mass spectral and HPLC analyses (M+H) 277; retention time 3.76 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:5]2=[CH:4][C:3]=1I)=[CH:13][C:12]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.[O:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[O:29]1[CH2:30][CH:31]=[C:32]([C:3]2[CH:4]=[C:5]3[C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:13]=4)[O:8][C:6]3=[N:7][C:2]=2[F:1])[CH2:33][CH2:34]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(C3=CCOCC3)cc12
Temperature: 120 °C

Procedure:
2-Fluoro-7-(2-fluoropyridin-3-yl)-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.151 g, 0.307 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.150 g, 0.71 mmol), tetrakis(triphenylphosphine)palladium (0.177 g, 0.153 mmol), and potassium phosphate (0.102 mL, 1.227 mmol) were suspended in dioxane (2 mL) and water (0.5 mL) and sealed in a microwave vessel under argon. The mixture was heated to 120° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure and partitioned between water (80 mL) and ethyl acetate (80 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (1-4% methanol in dichloromethane gradient) gave 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[C@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 10 %

Procedure:
Prepared in analogy to example 1 (b) from 2-((R)-sec-butoxy)-5-methanesulfonyl-benzoic acid (Example A20) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 10%). MS (m/e): 492.4 (M+H+, 100%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:25])([F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:7]([F:25])([F:24])[F:6])[N:15]=[CH:16][C:17]=12
Reactant: Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Phosphoryl trichloride (34.2 ml, 356.88 mmol) was added to 1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate P2) (5.0 g, 17.84 mmol). The resulting solution was stirred at 100° C. for 4 hours. The mixture was evaporated and the residue added to ice (˜200 g) with vigorous stirring. The mixture was stirred for 30 mins and the solid was collected by filtration washed with water (3×50 mL) and dried by suction. The solid was dissolved in ethyl acetate (250 mL), dried (MgSO4) and evaporated to give the product (4.5 g, 85%). 1H NMR (400 MHz, DMSO) δ 7.75-7.80 (1H, m), 7.88-7.91 (1H, m), 7.95-7.98 (1H, m), 8.05-8.07 (1H, m), 8.79 (1H, s), 8.88 (1H, s); m/z (ESI+) (M+H)+=299; HPLC tR=2.39 min.