Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27]>CCOCC>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27].[N:18]1([C:2]2[S:3][C:4]3[CH2:13][C@H:12]4[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]4[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=3[N:17]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: CCCN1CCC[C@H]2Cc3nc(Br)sc3C[C@@H]21
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Product: CCCN1CCC[C@H]2Cc3nc(N4CCCC4)sc3C[C@@H]21

Procedure:
A reaction mixture, prepared from 6.6 g. of trans-(±)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline and 20 ml. of pyrrolidine, was heated to reflux temperature for about 18 hours and was then cooled. The volatile constituents were removed in vacuo and the resulting residue diluted with water. The aqueous mixture was made strongly basic with concentrated aqueous ammonium hydroxide. The alkaline layer was extracted several times with equal volumes of chloroform. The chloroform extracts were combined, and the combined extracts washed with water and with saturated aqueous sodium chloride and were then dried. The solvent was evaporated therefrom in vacuo. TLC (9:1 CHCl3 /MeOH+a trace of aqueous ammonium hydroxide) showed one spot, more polar than starting material. The residue was therefore dissolved in chloroform and the chloroform solution chromatographed over a florisil column using chloroform as the eluant. Seventeen hundredths grams of a light yellow glass were obtained by this procedure. The glass was dissolved in ether and 0.06 g. of maleic acid in ethereal solution added thereto. A solid maleate salt precipitated. The ether was removed by decantation and the solid salt recrystallized from a mixture of ethanol and ether. Five hundredths grams of trans-(±)-2-(1-pyrrolidinyl)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline maleate were obtained melting with decomposition at 184° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:20])=[CH:6]1)(=[O:4])=[O:3].[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:9]1[CH2:10][CH:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:20])[C:8]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1cccs1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1cccs1)C2
Yield: 100.1 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.20 g), aminoguanidine hydrochloride (0.075 g), concentrated hydrochloric acid (0.032 ml), water (0.032 ml) and ethanol (30 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 18) (0.26 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([OH:32])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[C:24]([O:32][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(O)c2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 66.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.00 g, 5.74 mmol) and 3-(1-cyano-1-methylethyl)-N-[3-hydroxy-4-(trifluoromethyl)phenyl]benzamide (955 mg, 6.02 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.18 g, 8.61 mmol), and the mixture was stirred at 80° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (150 mL) was added, and the mixture was twice extracted with ethyl acetate/hexane (75 mL/75 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (1.79 g, 66%) as a yellow amorphous substance.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:5][CH:4]=1.C([C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH2:30][S:31](Cl)(=[O:33])=[O:32])C>N1C=CC=CC=1>[CH2:19]([C:18]1[CH:23]=[CH:24][CH:25]=[CH:10][C:11]=1[C:29]1([CH2:30][S:31]([N:2]([C:3]2[CH:4]=[CH:5][C:6]([N:9]3[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]4[C:18]5[C:23]([CH:24]=[CH:25][C:10]3=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:7][CH:8]=2)[CH3:1])(=[O:32])=[O:33])[CH:28]=[CH:38][CH:37]=[CH:36][CH2:35]1)[CH3:20]
Reactant: CCc1ccccc1CS(=O)(=O)Cl
Reactant: CNc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: CCc1ccccc1C1(CS(=O)(=O)N(C)c2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)C=CC=CC1
Yield: 27.9 %

Procedure:
5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40 mg, 0.121 mmol) obtained in Example 198, (1), and 2-ethylbenzylsulfonyl chloride (132 mg, 0.605 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to obtain the title compound (10 mg, yield 16%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]([CH3:25])=[N:18]1>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22]([C:21]2[N:17]([CH3:16])[N:18]=[C:19]([CH3:25])[CH:20]=2)=[O:23])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Yield: 89.6 %

Procedure:
In the same manner as in Reference Example 11 and using 3-aminophenol (2.11 g, 19.3 mmol), triethylamine (2.81 mL, 20.3 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.07 g, 19.4 mmol) and tetrahydrofuran (30 mL) as starting materials, the title compound (4.00 g, 90%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.N[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH2:17]1[C:18]2[C:14](=[CH:13][CH:12]=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: Nc1ccc2c(c1)CCC2
Agent: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCC2

Procedure:
2-Chlorobenzoyl chloride (11.8 g) was added dropwise to a stirred mixture of 5-aminoindan (9.0 g), potassium carbonate (9.3 g), ethyl acetate (90 ml) and water (90 ml) under ice-cooling. The mixture was further stirred under ice-cooling for one hour, at the end of which time the organic layer was separated, washed with water, dried (MgSO4) and distilled to remove the solvent. The procedure gave crystals of 5-2-chlorobenzoylamino)indan. The crystals were collected by filtration and recrystallized from isopropyl ether to give colorless needles, m.p. 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:34]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([C:43](=[O:44])[C@@H:42]([NH:41][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:46]([CH3:48])[CH3:47])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol), (S)-2-(Boc-amino)-3-methylbutyric acid (0.28 g, 1.29 mmol) and 4-ppy (9 mg, 0.06 mmol) in DMF (2 mL) was added EDCI (234 mg, 1.23 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc (30 mL) and washed with water (30 mL×3). The mixture was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=3/1 to 2/1) to afford the title compound as a white solid (41 mg, 29.1%). The title compound was characterized by LC-MS as shown below:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(NCc1cccnc1)c1ccc(Br)cc1

Procedure:
A solution of 4-bromo-α-methylbenzylamine (1.5 g, 7.7 mmol), 3-pyridinecarboxaldehyde (0.8 g, 7.5 mmol), and sodium triacetoxyborohydride (2.25 g, 10.5 mmol) in 60 ml of 1,2-dichloroethane was stirred at room temperature for 18 h. The solution was diluted with dichloromethane and washed twice with a saturated sodium bicarbonate solution, once with water, and once with brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 8.70 (m,2H), 7.85 (m,1H), 7.67 (d,2H,J=8 Hz), 7.45 (d,2H,J=8 Hz), 7.43 (m,1H), 3.95 (q,1H,J=8 Hz), 3.83 (q,ABX,2H), 1.57 (d,3H,J=8 Hz). MS calcd. 291.2; MS (M+1) 292.1.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I.O>O1CCCC1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][CH3:30])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.30 g) was added to a stirred solution of tetrahydrofuran (2 ml) and sodium hydride (62.8%, 0.04 g) with ice-cooling. After 30 minutes, a solution of methyl iodide (0.14 g) in tetrahydrofuran (2 ml) was added to that stirred solution at 0° C. The reaction mixture was stirred for 4 hours at room temperature, then poured into water (20 ml), extracted with chloroform (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine (trans isomer) (0.30 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=O)=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4](=[O:17])[CH2:3]1.CC1(C)C2C(=CC(C(O)=O)=CC=2)[NH:23]C(=O)C1.CC1(C)C2C(=CC(C#N)=CC=2)NC(=O)C1.ICC.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:23])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4](=[O:17])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(C(=O)O)ccc21
Reactant: CCN1C(=O)CC(C)(C)c2ccc(C(=O)O)cc21
Agent: CC1(C)CC(=O)Nc2cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCN1C(=O)CC(C)(C)c2ccc(C#N)cc21
Temperature: 25 °C
Yield: 48 %

Procedure:
One prepared 4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid analogously to the procedure for 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (DE-A-3,818,830) as follows: one stirred 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarbonitrile (2.0 g, 10.0 mmol), iodoethane (1 ml, 12.0 mmol) and potassium carbonate (1.70 g, 12.0 mmol) for one hour at 60° C., again added iodoethane (2 ml, 24 mmol) and potassium carbonate (2.5 g, 25 mmol) thereto and stirred for one hour at 60° C. One allowed to cool to room temperature, stirred the solution into water, filtered off the precipitate with suction and dried in a vacuum. One obtains 4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarbonitrile (1.1 g, 48%) with the m.p.=120°-121° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:36][C:32]2[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=2)[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Cc1cccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc12
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C)cccc23)n[nH]1
Temperature: 100 °C
Yield: 13 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methylquinazoline (0.255 g, 0.79 mmol) in DMA (2 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester prepared according to US2007/219195 (0.31 g, 1.58 mmol) and acetic acid (0.15 mL) and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and then was purified by reverse phase HPLC using an ammonium acetate modifier. Fraction 1 containing pure product were combined, treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM and the combined extracts were washed with saturated aq NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (br s, 1H), 10.57 (s, 1H), 8.67 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.92-8.11 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 5.96 (s, 1H), 2.59 (s, 3H), 2.17 (s, 3H); LC-MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: Cl[Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1.CCN(CC)CC.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CCCCCC>[CH:30]1([NH:36][Si:2]([CH3:22])([CH3:21])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCCC1
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[Si](C)(NC1CCCCC1)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl) silane (3.8523 g, 0.01182 moles) was stirred in hexane (100 mL) as NEt3 (1.5136 g, 0.01496 moles) and cyclohexylamine (1.2107 g, 0.01221 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (4.3313 g, 94.5 percent).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].CC1C=CC(S(O[CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)cc1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of 60% sodium hydride (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) dropwisely. The solution was added with 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 2.10 g, 21.8 mmol) dropwisely. The reaction was stirred at 65° C. for 16 h. The solution was cooled to room temperature, poured into icy H2O, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly for the next step without further purification.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:35]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:35])=[O:24]
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@]1(OC(=O)c2ccco2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (6.20 g) is dissolved in ethyl acetate (100 mL). DBU (2.20 g) and dimethyl sulphate (1.83 g) are added sequentially. The reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords furan-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 3.75 (3H, s), 6.30 (1H, dd), 6.45 (1H, d), 6.55 (2H, m), 7.15 (1H, d), 7.60 (1H, d).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]([CH3:44])[C:41]([NH2:43])=[O:42])#[CH:33].F[B-](F)(F)F.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:43][C:41](=[O:42])[CH:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:32]#[C:33][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1)[CH3:44]
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A70 (0.397 g, 0.867 mmol), 2-(2-ethynylphenyl)propanamide K7 (0.195 g, 1.13 mmol), CuI (0.011 g, 0.057 mmol), PdCl2(PPh3)2 (0.039 g, 0.056 mmol) and t-Bu3PH.BF4 (0.017 g, 0.058 mmol) under a nitrogen atmosphere was added dioxane (12 mL) and DIPEA (0.60 mL, 3.4 mmol). The mixture was stirred at room temperature for 96 hours before being concentrated under reduced pressure and purifying by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. and 0-20% MeOH in EtOAc) to give the title compound A71 (0.139 g, 27%). LCMS-D: rt 3.626 min; m/z 595.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[N:12]=3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CN1CCCC1C
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CN1CCCC1C

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 9 using 2-(4-Bromo-phenyl)-5-methyl-4-(2-methyl-pyrrolidin-1-ylmethyl)-oxazole (See Example 99) and 4-methylsulfonylphenylboronic acid. MS (m/e) 411.2 (M+1).