Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([OH:22])=[N:16]1.C(N(CC)CC)C.[F:30][C:31]([O:35][C:36]([F:39])([F:38])[F:37])=[C:32]([F:34])[F:33].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][C:32]([F:34])([F:33])[CH:31]([F:30])[O:35][C:36]([F:39])([F:38])[F:37])=[N:16]1
Reactant: COc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: FC(F)=C(F)OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F

Procedure:
1.5 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxy-5-methoxypyrazole was dissolved in 30 mL of N,N-dimethylformamide, 40 g of triethylamine was added, and stirring was carried out at 50° C. for 3 hours while trifluoromethyl trifluorovinyl ether was blown. To this solution, ethyl acetate was added, followed by washing with a saturated aqueous solution of citric acid, and then the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.1 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxy-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]([C:13](=[O:56])[NH:14][CH2:15][C:16](=[O:55])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[C:43]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:44])[N:36]([CH2:51][CH2:52][O:53][CH3:54])[CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH:20]=1)[CH:10]([CH3:12])[CH3:11])(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C@@H:9]([CH:10]([CH3:12])[CH3:11])[C:13]([NH:14][CH2:15][C:16](=[O:55])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[C:43]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[O:44])[N:36]([CH2:51][CH2:52][O:53][CH3:54])[CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH:20]=1)=[O:56]
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(C(=O)N3CCOCC3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)CNC(=O)[C@@H](N)C(C)C)ccc3F)CC2)c2c(C(=O)N3CCOCC3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4N HCl in dioxane (2.5 mL) was added to ((S)-1-{[(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-methyl]-carbamoyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (0.94 mg, 0.12 mmol). The resulting colorless solution was stirred under N2 at rt overnight. The reaction mixture was concentrated in vacuo and the residue was triturated with Et2O (10 mL). The ethereal layer was removed and the pale yellow solid washed with Et2O (3×10 mL). The solid was dried under vacuum to afford the product (85 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ 8.74-8.71 (m, 1H), 8.54-8.51 (m, 1H), 8.20 (br s, 2H), 7.7.63-7.60 (m, 1H), 7.44-7.36 (m, 1H), 7.32-7.21 (m, 1H), 7.13-7.05 (m, 1H), 7.01-6.98 (d, 1H), 4.39 (t, 2H), 4.25 (d, 2H), 4.21-4.15 (m, 1H), 3.88-3.83 (m, 2H), 3.79-3.77 (m, 1H), 3.69 (t, 2H), 3.62 (br s, 2H), 3.24 (s, 3H), 3.08-2.88 (m, 2H), 2.10-2.03 (m, 1H), 1.85-1.60 (m, 6H), 1.11-1.07 (m, 1H), 0.94 (d, 6H); MS m/z: [M+H]+=679.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: OCc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A solution of 4.59 g (36.9 mmol) of 5-fluoro-2-hydroxybenzyl alcohol [CAS 2357-33-7] in 200 ml of dry acetonitrile is mixed with 10.0 g (36.9 mmol) of 4-chloromethyl-4′-trifluoromethylbiphenyl and 6.13 g (44.3 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After concentration, the resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5:1). 11.8 g (32.9 mmol, 89% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O.CN(C)C=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([Cl:25])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.61 g (5.7 mmol) of 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (60 mL), and 3.5 mL (42 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (60 mL), and 0.71 g (6.3 mmol) of 1,3-cyclohexanedione and 0.97 mL (6.9 mmol) of triethylamine were added to the above solution. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 2.13 g of the title compound was obtained as a light yellow solid (yield: quantitative).
Reaction SMILES: [S:1](=[C:4]1[CH:9]=[CH:8][O:7][C:6]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:11])=[CH:5]1)(=[O:3])=[O:2].O.O[Li].O>C1COCC1>[S:1](=[C:4]1[CH:9]=[CH:8][O:7][C:6]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:11])=[CH:5]1)(=[O:2])=[O:3]
Reactant: COC(=O)c1ccc(OC(=O)c2cc(=S(=O)=O)cco2)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)c2cc(=S(=O)=O)cco2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-[4-sulfonylpyranoyloxy]-2-methoxybenzoate (470 mg, 1.5 mmol)in THF:H2O (18 mL: 2 mL) was added LiOH.H2O (128 mg, 3 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid passed through a plug of silca gel packed in 80:20 hexanes:EtOAc and eluted with same. The solvent was removed under reduced pressure to afford 4-[4-sulfonylpyranoyloxy]-2-methoxybenzoic acid as a white solid.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35]N)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:30]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (3-methane sulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=459.3 (M+H)+
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Product: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (620 mg, 1.60 mmol) is coupled to 4′-bromo-2,2,2-trifluoroacetophenone (400 mg, 1.60 mmol) using Method B to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH2:7]O)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC1C(OC)=CC(CBr)=C([N+]([O-])=O)C=1.[I-:55].[Na+]>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH2:7][I:55])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: [I-]
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OC
Agent: BrC(Br)(Br)Br
Agent: COc1cc(CBr)c([N+](=O)[O-])cc1OC
Agent: [Na+]
Product: COc1cc(CI)c([N+](=O)[O-])cc1OC

Procedure:
The reaction of 4,5-dimethoxy-2-nitrobenzyl alcohol, carbon tetrabromide and triphenylphosphine is used to generate 4,5-dimethoxy-2-nitrobenzyl bromide, which is then treated with sodium iodide to give 4,5-dimethoxy-2-nitrobenzyl iodide (2).
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:3][C@@H:4]([CH2:16][N:17](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][Si:2]([CH3:36])([C:32]([CH3:34])([CH3:33])[CH3:35])[O:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](COc1cccc2nc[nH]c12)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)COc1cccc2nc[nH]c12

Procedure:
(S)-4-[2-(Dimethyl-tert-butylsilyl)oxy-3-(dibenzylamino)propoxy]benzimidazole (1.27 g. 2.5 mmol) was dissolved in methanol (140 mL) and treated with an excess of ammonium formate (1.64 g, 25.0 mmol) followed by 10% palladium on carbon (410 mg). The resulting suspension was stirred at reflux for 1 hour. After cooling, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to a brown oil (780 mg, 97%). NMR.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])[C:25](O)=[O:26])(=[O:22])[CH3:21]>>[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])[C:25]([NH:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)S[C@H](C(=O)O)[C@@H](C)C(C)C
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)[C@@H](SC(C)=O)[C@@H](C)C(C)C)CCc2ccccc21
Yield: 49 %

Procedure:
0.500 g (1.91 mmol) of (3S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one and 0.430 g (2.1 mmol) of (2S,3S)-2-acetylthio-3,4-dimethylpentanoic acid were treated by the same method as that of Example 101(h). Thus, 0.420 g of the title compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC
Agent: Cl
Product: NCC(CP(O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 5.0 g of ethyl 3-amino-2-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate in 60 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 h. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-(4-chlorophenyl)propylphosphonous acid (1/3M H2O), m.p. 235°-240° C., 31P=+23.9 ppm (D2O).
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:34]>C(Cl)(Cl)Cl>[Si:8]([O:16][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:34])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: O=C1c2cccc3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Triethyl amine (0.4 g, 4.0 mmol) and tert-butyldimethylsilyl chloride (0.6 g, 4.0 mmol) were added to a solution of 2-hydroxy-5-nitro-benzo[de]isoquinoline-1,3-dione (1.0 g, 3.9 mmol, from Example 1) in chloroform (10 mL). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo to give a dark residue. Column chromatography (silica gel 2% methanol in chloroform) gave 1.1 g of the title compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1([C:8]2[CH:33]=[CH:32][C:11]([CH2:12][N:13]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)C(=O)C(F)(F)F)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)#[N:4].O>C(O)C>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]#[N:4])[CH2:6][CH2:7]3)=[CH:33][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: N#CC1(c2ccc(CN(CCc3cccc(C(F)(F)F)c3)C(=O)C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
46 mg (1.23 mmol) of sodium borohydride were added to 135 mg (0.31 mg) of N-[4-(1-cyano-cyclopropyl)-benzyl]-2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide dissolved in 3.1 ml ethanol under nitrogen. The reaction mixture was stirred at rt for 3 h. Under ice bath cooling water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (25 g silica gel; methylene chloride/methanol=19:1) to yield 81 mg (77%) of 1-(4-{[2-(3-trifluoromethyl-phenyl)-ethylamino]-methyl}-phenyl)-cyclopropanecarbonitrile as a colorless oil. 1HNMR (DMSO-d6, 300 MHz): δ 7.61-7.47 (m, 4H), 7.30 (d, 2H), 7.24 (d, 2H), 3.69 (s, 2H), 2.81 (t, 2H), 2.73 (t, 2H), 1.72 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:69][CH:70]1[CH2:72][NH:71]1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:71]2[CH2:72][CH:70]2[CH3:69])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CN1c1c(C=O)c2ccccc2n1-c1ccc(C(C)(C)C)cc1
Yield: 65.6 %

Procedure:
A side-arm tube under a nitrogen atmosphere is charged with 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (100 mg, 0.321 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (20 mg, 0.032 mmol) and sodium tert-butylate (46 mg, 0.479 mmol). To this is added toluene (3.0 mL), a solution of 2-methylaziridine (37 mg, 0.678 mmol) in toluene (1.0 mL) and the resulting mixture is stirred overnight at 80° C. The reaction is cooled, water added and the mixture is extracted with ethyl acetate. The combined ethyl acetate layer are washed with water, with brine, dried over sodium sulfate, filtered and the solvent concentrated to give an oil that is purified by chromatography eluting with heptane-5 to 30% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-(4-tert-butyl-phenyl)-2-(2-methyl-aziridin-1-yl)-1H-indole-3-carboxaldehyde (70 mg, 66% yield) as a yellow solid. TLC (heptane-30% ethyl acetate/) Rf 0.20; ESI/MS 333 (M+H); RT 4.15 min; NMR 10.16 (1H, s); 8.08 (1H, d, J=6 Hz); 7.70 (2H, d, J=9 Hz); 7.49 (2H, d, 9 Hz); 7.21 (2H, m); 6.91 (1H, d, J=9 Hz); 2.43 (2H, m); 2.28 (1H, d); 1.38 (9H, s); 0.79 (3H, d, J=6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: Oc1ccc(F)cc1Br
Reactant: BrCC1CC1
Product: Fc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-fluoro-phenol and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22](Cl)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:30](=O)([O-])[O-:31].[K+].[K+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]([O:31][CH3:30])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(Cl)c2ccncc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 60 °C

Procedure:
A suspension of 4-tert-butyl-N-[4-chloro-2-(chloro-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide (113 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.5 mmol) in anhydrous methanol was heated at 60° C. overnight, the solid residue was then removed by filtration and product was purified by preparative HPLC. MS: (M+H)=445.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[CH2:13][C:14]3[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1>>[CH3:20][N:12]([CH2:11][C:9]1[S:10][C:5]2[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][C:2]([C:35]3[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=3)=[N:7][C:6]=2[CH:8]=1)[CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN(Cc1cn(C)cn1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cn(C)cn1)Cc1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1
Yield: 49 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-1H-imidazol-4-ylmethyl)-amine was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by flash column chromatography using 10% methanol/ethyl acetate as the eluent to give 295 as a solid (49% yield). NMR (DMSO, 400 MHz), 2.19 (3H, s), 3.62 (2H, s), 3.68 (3H, s), 3.75-3.78 (4H, m), 3.85 (2H, s), 3.93-3.97 (4H, m), 6.85 (1H, s), 7.04 (2H, s), 7.36 (1H, s), 7.58 (1H, s), 9.11 (2H, s). MS: (ESI+): MH+=452
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.[CH:19]([N:32]1[CH2:35][C:34](OS(C)(=O)=O)([CH3:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:19]([N:32]1[CH2:35][C:34]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[F:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)([CH3:36])[CH2:33]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(N)cc3N21
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1C(=O)NN=C2COc3cc(F)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
A mixture of 6-amino-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #56, Step F, 0.100 g, 0.400 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (Preparation #3, Step B, 0.159 g, 0.480 mmol) and K2CO3 (0.166 g, 1.199 mmol) in DMF (2 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to ambient temperature and poured into water (8 mL). The aqueous mixture was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a white solid (0.055 g, 28%). LC/MS (Table 1, Method 2) Rt=1.199 min.; MS m/z: 486 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1([NH:31]S(C(C)(C)C)=O)[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][CH2:18]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([C:8]1([NH2:31])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:19][CH2:18]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)NC1(Cc2ccccc2)CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(Cc2ccccc2)CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 130 °C
Yield: 22.1 %

Procedure:
120 mg of 2-methyl-propane-2-sulfinic acid [1-benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexyl]-amide (0.23 mmol) were dissolved in 2 ml of trifluoroacetic acid in a sealed microwave tube and heated in a microwave reactor for 1 h at 130° C. The solvent was removed under reduced pressure and the resulting residue purified by reversed phase HPLC chromatography. 21 mg of 1-benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexylamine were obtained as a solid (17%).