Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>C1C=CC=CC=1>[CH3:9][CH:10]1[C:2]2[C:1](=[C:6]([OH:7])[CH:5]=[CH:4][C:3]=2[CH3:8])[C:12](=[O:13])[CH2:11]1
Reactant: O=C1CCCO1
Reactant: Cc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(O)c2c1C(C)CC2=O

Procedure:
Likewise, a mixture of 21.6 g. (0.2 mol) of p-cresol and 17.2 g. (0.2 mol) of γ-butyrolactone is added into a mixture of 79.8 g. (0.6 mol) of anhydrous aluminium chloride and 15.0 g. (0.26 mol) of sodium chloride which mixture has been molten at 140°C, and the resultant mixture is heated at a temperature of 140°-200°C for about 3 minutes. After cooling, the reaction mixture is poured into a hydrochloric acid-ice and the resulting acidic solution is stirred with benzene. The benzene layer is taken up and dried with anhydrous sodium sulfate. The solvent is removed by distillation, and the residue is further subjected to vacuum distillation, whereby yellowish liquid is distilled out at 95°-105°C/2mmHg, which liquid is solidified on cooling. Upon recrystallization from n-hexane after decolorization with active carbon, 14.9 g. of whitish-purple crystals of 3,4-dimethyl-7-hydroxyindan-1-one having a melting point of 52°-53°C is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.5) (0.5 g, 1.62 mmol) and commercially available 3-bromo-benzene-boronic acid (0.42 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.54 g, 78%). MS (EI) 430.0 [(M)+]; mp 98.5° C.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C@H:16]1[NH:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])([CH3:14])[C@@H:12]([C:30]([O:32][CH3:33])=[O:31])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)[OH:35]>O1CCOCC1.O>[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][C:22]([O:24][CH2:25][C:26]([Cl:28])([Cl:29])[Cl:27])=[O:23])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:30]([O:32][CH3:33])=[O:31])[CH2:4][C@@H:3]1[OH:35]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2α,3α-epoxy-11α-(2,2,2-trichloroethoxycarbonylamino)-5α-androstane-17β-carboxylate (522 mg) in dioxan (5 ml) was treated with 2N sulphuric acid (1 ml) and stirred at ambient temperature for 18 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×). The extract was washed with water, dried and evaporated to give a foam. This was purified by preparative t.l.c. in ethyl acetate/petrol (1:1) and crystallised from ether to give the title compound (217 mg) m.p. 228°-230°, [α]D +27.6.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C(O)C>[S:19]1[CH:20]=[CH:21][N:22]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=3)[N:17]=[C:18]12
Reactant: Nc1nccs1
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3ccsc3n2)cc1
Yield: 31 %

Procedure:
A mixture of 38 g of ethyl 4-(chloroacetyl)phenylacetate, 60 ml of ethanol and 32 g of 2-aminothiazole is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated. To the residual reddish brown oil are added benzene and isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from ethanol to give 14 g of ethyl 4-(imidazo[2,1-b]-thiazol-6-yl)phenylacetate as colorless crystals melting at 117°-119°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][NH2:11]>C1COCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:11][CH3:10])[N:3]=1
Reactant: CN
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: CNc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. mixture 2,4,6-trichloropyrimidine (0.50 g, 2.7 mmol) in THF (3 mL) was added methyl amine (2M THF, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 30 minutes, at which time LCMS indicated the formation of the desired product. The reaction mixture was treated with water (10 mL) and extracted with EtOAc (2×10 mL). The organics were washed with brine (10 mL), dried (Na2SO4), and evacuated. The crude material was purified by column chromatography (Gradient from 0-30% EtOAc in Hexanes) to afford 180 mg (1.01 mmol, 38%) of 2,6-dichloro-N-methyl-4-pyrimidinamine and 150 mg (0.85 mmol 31%) of 4,6-dichloro-N-methyl-2-pyrimidinamine. MS (ES+) m/e 178 [M+H]+ for each.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:26]([OH:28])=[O:27])=[CH:12][N:13]2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)=[CH:8][C:7]=1[F:30].[CH3:31]O>>[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:26]([O:28][CH3:31])=[O:27])=[CH:12][N:13]2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)=[CH:8][C:7]=1[F:30]
Reactant: O=C(O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O

Procedure:
To 25 ml of methanol was added dropwise 1 g of thionyl chloride. To the solution was added 1.1 g of 7-chloro-6-fluoro-1-(4-fluoro-3-nitrophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. The solution was heated at reflux overnight. The reaction solution was allowed to cool down and concentrated in vacua. Diethyl ether was added to the residue. The solid was collected by filtration to give 1.4 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C:24]2=[O:29])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Reactant: CN1CCN(c2ccc(N)cc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4CCN(C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 16.5 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 12.5 parts of 1-(4-aminophenyl)-3-methyl-2-imidazolidinone, 11 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred and refluxed for 24 hours. After cooling, 100 parts of water were added and the whole was stirred. The precipitated product was filter off, washed with water and with 1-butanol and dried, yielding 17.5 parts (73%) of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2-imidazolidinone; mp. 240.9°-241.0° C. (28).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Br)=[O:32])=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([CH3:26])=[CH:28][CH:29]=4)=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1ccc(C(=O)Br)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 318 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-methyl benzoyl bromide. The compound of example 318 was used directly without isolation, for the preparation of compound of example 319.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10](/[CH:12]=[CH:13]/[CH2:14]P(OCC)(OCC)=O)=[O:11].[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=O.Cl>O1CCCC1.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]([CH3:23])=[CH:14][CH:13]=[CH:12][C:10]([O:9][CH2:8][CH3:7])=[O:11])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=C(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A stirred solution of 25.3 grams (0.230 mole) of potassium tert.-butoxide in 250 mL of tetrahydrofuran was cooled to 0° C., and a solution of 56.5 grams (0.230 mole) triethyl 4-phosphonocrotonate in 50 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature at about 0°-10° C. The complete addition required about 30 minutes. The reaction mixture was then stirred for one hour at 0°-5° C., and then 26.6 grams (0.180 mole) of 4-methoxyacetophenone was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was made acidic with an aqueous 2N hydrochloric acid solution and diluted with about 200 mL of water. The mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was taken up in 150 grams of silica gel, and the solvent was removed under reduced pressure. The silica gel mixture was placed on top of a column of silica gel, and the mixture was eluted with 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.9 grams of ethyl 5-(4-methoxyphenyl)-2,4-hexadienoate. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12]C)=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:10]([C:2]2[CH:3]=[CH:4][C:5]([C:7]([O:9][C:5]([CH3:7])([CH3:6])[CH3:4])=[O:8])=[CH:6][N:1]=2)=[O:12])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)[O-])cn1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
In step B, the 2,5-pyridinedicarboxylic acid, 2-methyl ester, 5-t-butyl ester (5) is amidated with morpholine to give the corresponding 6-(morpholine-4-carbonyl)nicotinic acid, t-butyl ester (6).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[Br:13].C([O-])([O-])=[O:15].[Ca+2]>O1CCOCC1.O>[OH:15][CH2:2][C:3]1[C:8]([Br:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[Br:13]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)c(CBr)c(Br)c1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(CO)c(Br)c1

Procedure:
A mixture of 1-bromomethyl-2,6-dibromo-4-nitrobenzene (4.45 g, 1 eq.) and CaCO3 (5.7 g, 5 eq.) in 1,4-dioxane (20 mL) and water (20 mL) was heated to and maintained at reflux overnight. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrousmgSO4, filtered and concentrated. The product was purified by silica gel chromatography (eluted with 4:1 hexanes:ethyl acetate) to give 1-Hydroxymethyl-2,6-dibromo-4-nitrobenzene. 1H NMR (500 MHz, CDCl3) δ CHCl3: 2.28 (1H, broad t), 5.05(2H, m), 8.397(2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]cnc23)C1

Procedure:
EXAMPLE 102 was prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (EXAMPLE 79, Step 3) and 6-chloro-9H-purine:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6](F)=[N:7][CH:8]=1)#[N:2].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1>>[CH3:10][C:5]1[C:6]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH3:11])=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: Cc1cc(C#N)cnc1F
Reactant: CC1CCCCN1
Product: Cc1cc(C#N)cnc1N1CCCCC1C
Yield: 92.7 %

Procedure:
A solution of 5-cyano-2-fluoro-3-methylpyridine (Molekula, 1.50 g; 11.02 mmol) and 2-methylpiperidine (5.20 mL; 44.08 mmol) was heated to 90° C. for 18 h. Reaction mixture was extracted with EtOAc, the organics dried over MgSO4, evaporated under vacuum to give the title compound as a brown oil (2.2 g, 93%). 1H NMR (DMSO-d6) δ 8.46 (d, J=2.3 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 4.01-3.96 (m, 1H), 3.37-3.25 (m, 2H), 3.17-3.09 (m, 1H), 2.22 (s, 3H), 1.72-1.46 (m, 6H), 1.11 (d, J=6.6 Hz, 3H). HPLC (Method B) Rt 3.60 min (Purity: 84.5%). LC/MS (Method A): 216.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:19]>O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1

Procedure:
To a solution of 2-amino-9-(2-hydroxyethoxymethyl) adenine (0.22 g) in water (30 ml) was added a suspension of adenosine deaminase in aqueous ammonium sulfate (0.44 ml, containing 4.4 mg of the enzyme). The reaction mixture, which initially had a pH of 7.0, was heated at 37° C. for 18 hours, at which time the pH was 8.5 and TLC (silica gel plates developed in 15% methanol - 85% chloroform) indicated a single product different from starting material. The reaction mixture was thoroughly chilled in an ice bath and the resulting white solid removed by filtration and thoroughly washed with cold water. The product was dried at 100° C./0.1 mm Hg for 16 hours to give 0.20 g of 9-(2-hydroxyethoxymethyl)guanine. 1/4 H2O, the structure of which was confirmed by m.p., TLC, U.V., NMR and mass spectroscopy analysis. Recrystallization from methanol gave the anhydrous 9-(2-hydroxyethoxymethyl)quanine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].COC(=O)[C:56](Cl)([F:58])[F:57].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH:56]([F:58])[F:57])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:26]=3)[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: COC(=O)C(F)(F)Cl
Reactant: CCOC(=O)N1c2ccc(O)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(OC(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 75 °C
Reaction time: 17 h
Yield: 93.8 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg), cesium carbonate (55 mg) and 2-chloro-2,2-difluoroacetic acid methyl ester (44 mg) are dissolved in N,N-dimethylformamide (1 ml) and stirred at 75° C. for 17 hours. The reaction solution is cooled to room temperature, and thereto are added an aqueous citric acid solution and ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-difluoromethoxy-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (101 mg). MS (m/z): 705 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([CH3:41])[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[O:29])[N:33]([CH3:41])[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(F)(F)F
Reactant: NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Temperature: 85 °C
Yield: 39 %

Procedure:
5-Fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzylamine, (6v) (50 mg, 0.15 mmol), (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (a), (68 mg, 0.21 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) were combined in DMF (1.5 mL) and heated at 85° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 4% MeOH/CH2Cl2/0.5% Et3N) to provide 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzyl]-urea (7v) (30 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.03-6.80 (m, 4H), 6.11 (s, 1H), 5.93 (s, 1H), 5.25 (t, J=8.6 Hz, 1H), 4.38 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 3.67 (s, 3H), 2.61 (s, 4H), 1.81 (s, 4H), 1.26 (s, 9H); MS (APCI+) m/z 521 (M+H) detected; HPLC (5 to 95%) 2.61 min.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)[C:3]#[N:4].Cl.C(=O)([O-])[O-:13].[Na+].[Na+]>>[NH2:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)[C:3]([NH2:4])=[O:13]
Reactant: N#CC(N)c1cncnc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)C(N)c1cncnc1
Yield: 81 %

Procedure:
Amino (pyrimidin-5-yl)acetonitrile (1.1 g, 8.2 mmol) is hydrolyzed by refluxing in a small volume of dilute HCl for 1 hour. The pH is raised to 10 by addition of saturated sodium carbonate and the mixture then extracted with chloroform. Evaporation of the chloroform and chromatography (silica, chloroform/methanol) gives product as a yellow solid 950 mg (81%) ms m/z=142.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([S:15][CH3:16])[CH:14]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][S:15][C:13]1[CH:14]=[C:9]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[CH:10]=[N:11][CH:12]=1
Reactant: CSc1cncc(Br)c1
Reactant: C#Cc1cccc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CSc1cncc(C#Cc2cccc(C#N)c2)c1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
Add copper (I) iodide (20.0 mg, 0.18 mmol), bis(triphenylphosphine)palladium (II) dichloride (64.2 m g, 0.092 mmol) and triethylamine (1.03 mL, 7.32 mmol), to a solution of 3-bromo-5-methylsulfanylpyridine, (prepared as described in PREPARATION 29), (375 mg, 1.83 mmol) and 3-ethynylbenzonitrile, (prepared as described in PREPARATION 8), (465 mg, 3.66 mmol) in ethyl acetate (3 mL) and stir at 90° C. overnight. Cool to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes/ethyl acetate, to give the title compound (187 mg, 41%).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (106 mg, 0.31 mmol) in dichloromethane (10 mL) was added triethyl amine (0.130 mL, 0.933 mmol) followed by dimethylcarbamic chloride (0.043 mL, 0.46 mmol), under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give 3-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-1,1-dimethylurea, (405), (63 mg 49%). 1H NMR (300 MHz, CDCl3) ppm 2.01-2.16 (m, 2H) 2.20-2.37 (m, 2H) 2.85 (s, 6H) 3.00-3.15 (m, 4H) 4.12-4.25 (m, 2H) 5.78 (s, 1H) 6.62 (s, 2H) 7.10-7.22 (m, 5H) 7.23-7.34 (m, 5H)