Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 90 °C

Procedure:
The mixture of 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (11.2 mg, 0.027 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (5.2 mg, 0.027 mmol) in 1 mL of isopropanol was heated to 90° C. for 1 hour. The solvent was evaporated and the residue was re-dissolved in a mixture of methanol and CH2Cl2 (1:1, v/v) and applied onto a prep-TLC plate (2000 micro). The plate was developed in NH4OH/MeOH/CH2Cl2 (1:9:90, v/v). 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 1) was obtained as a yellow solid (8.6 mg, 61%). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.52 (s, 1H), 7.44 (m, 2H), 7.28 (s, 1H), 7.19 (m, 3H), 6.66 (m, 2H), 4.40 (q, 2H), 3.00-3.18 (m, 8H), 2.60 (m, 4H), 2.35 (s, 3H), 2.22 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N6O3: 525.25 (M+H), Found: 525.4.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[Cl:32][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(C#N)c(Cl)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 69 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-chlorobenzonitrile (0.288 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.075 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.18 g).
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Product: CC(=O)Oc1ccc(C)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
A solution of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (0.9 g) in acetylchloride (20 ml) is stirred at room temperature for 18 h. The acetyl chloride is evaporated, ether is added, and the precipitate of 2-(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl acetate hydrochloride is filtered off; mp 126-130° C. Anal Calcd for C24H33NO2.HCl: C, 71.35; H, 8.48; Cl, 8.78; N, 3.47. Found: C, 71.02; H, 8.30; Cl, 8.64; N, 3.43. [α]D (c=1, MeOH) +11°.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[Cl:12][C:13]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1cccc(C(F)(F)F)c1Cl

Procedure:
The title compound, yellow solid, MS: m/e=361.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-chloro-3-trifluoromethylbenzoic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:2]([CH3:4])[CH3:3].NC(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[N+:8]([O-:18])[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NC(N)=O
Reactant: COC(=O)c1cncc(OCC(C)C)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(OCC(C)C)c[n+]([O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 127.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 5-isobutoxynicotinate (5.13 g), urea-hydrogen peroxide adduct (4.84 g) and acetonitrile (82 mL) was added trifluoroacetic anhydride (8.25 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and washed with acetonitrile. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (7.04 g) as a white amorphous solid. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]([F:17])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][CH2:21][CH2:22][OH:23])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 81.7 %

Procedure:
Using 3.5 g (13.8 mmol) of 4-trifluoromethoxy-4'-hydroxybiphenyl, 45 ml of acetonitrile, 2.01 g (14.5 mmol) of 3-bromo-1-propanol and 3.81 g (27.5 mmol) of anhydrous potassium carbonate, synthetic treatment was carried out in the same manner as in Example 2. The obtained gray powder was recrystallized from benzene/n-hexane to obtain 3.52 g (yield: 82%) of 4-trifluoromethoxy-4'-(3-hydroxypropoxy)biphenyl (21) as a colorless powder.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH2:39][CH:40]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:40][CH2:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 6.4 g of methoxymethyl-triphenylphosphonium chloride in 80 ml of t-butyl methyl ether was treated within 3 minutes with 2.1 g of potassium t-butylate while gassing with argon at 0° C. and the mixture was stirred for a further 1 hour at 0°-5° C. The mixture was then treated dropwise within 5 minutes at 0° C. with a solution of 3.0 g of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde in 20 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 2 hours at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The residue was dissolved in 15 ml of ethyl acetate and the clear solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (5.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 2.95 g (88%) of p-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]benzonitrile as colourless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
0.1 g (0.26 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of DMAP, 80 mg (0.784 mmol) of N-methylpiperazine are added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is chromatographed over silica gel (dichloromethane/methanol 9:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:13]([OH:15])=O)=[C:10](C)[N:11]=2)[CH:2]=1.[NH2:16]C1C=CC=CC=1>S(Cl)(Cl)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:13]([NH2:16])=[O:15])=[CH:10][N:11]=2)[CH:2]=1
Reactant: Cc1nc(-c2cccnc2)sc1C(=O)O
Reactant: Nc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cnc(-c2cccnc2)s1
Temperature: 82 °C

Procedure:
2-(3-Pyridyl)-4-methylthiazole-5-carboxylic acid (0.61 g, 2.8 mmol) was dissolved in thionyl chloride (2 mL) and the mixture was stirred with heating (82° C., 3 hours). Upon cooling, the solvent was removed and the residue was dried under high vac. The acid chloride was then suspended in 5 mL of pyridine and added to a microwave vial charged with 2-(3-morpholinomethyl)imidazo[2,1-b]thiazol-6-yl)aniline (0.87 g, 2.8 mmol). The reaction was subjected to microwave irradiation (160° C., 15 min). The solution was triturated with methanol, and the resulting solid was filtered and washed with additional methanol. The solid was dried to afford 0.97 g (68%) of 4-methyl-N-(2-(3-morpholinomethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)-2-(pyridin-3-yl)thiazole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)Nc3ccc(F)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(Cl)c1)N1CCN(C[C@H]2CNCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl (2S)-2-[(4-{[(3-chloro-4-fluorophenyl)amino]carbonyl}piperazin-1-yl)methyl]morpholine-4-carboxylate (9.867 g, 21.6 mmol) in dichloromethane (100 ml) was added TFA (100 ml). The reaction was allowed to stir at ambient temperature for 2 hours. The solvents were then removed in vacuo, residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to dryness to give the product as an off white solid (7.69 g, 21.6 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[Cl:17][C:18]1[CH:19]=[C:20]([C@H:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=2[F:39])=[O:29])[CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=1>>[NH2:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([NH:27][C@@H:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)[CH2:25][OH:26])=[O:29])=[C:31]([F:39])[CH:32]=2)=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:15])[N:12]([CH3:14])[CH2:13]2)=[CH:6][N:7]=1
Reactant: O=C(N[C@H](CO)c1cccc(Cl)c1)c1ccc(B(O)O)cc1F
Reactant: CN1CC(c2cnc(N)c(Br)c2)CCC1=O
Product: CN1CC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)CCC1=O

Procedure:
Following Step 6 in Scheme 47, using 5-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one and (S)-(4-((1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)boronic acid, 4-(2-amino-5-(1-methyl-6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained (33%). LCMS (m/z): 497.2 (MH+), 0.61 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.70 (m, 1H), 7.98 (m, 1H), 7.88 (m, 2H), 7.44 (m, 3H), 7.36 (m, 2H), 7.30 (m, 1H), 5.19 (m, 1H), 3.88 (m, 2H), 3.51 (m, 2H), 3.21 (m, 1H), 2.97 (s, 3H), 2.50 (m, 2H), 2.07 (m, 2H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), EtOH+0.1% DEA=40%, 5 ml/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained at Rt=2.22 min. LCMS (m/z): 497.2 (MH+), 0.61 min. The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained at Rt=3.09 min. LCMS (m/z): 497.3 (MH+), 0.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 90 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3 mmol) and phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) in the manner described in Example 115C. The final product was purified by column chromatography (25-100% EtOAc/hexanes then 5-10% MeOH/DCM) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (150 mg, 0.27 mmol, 90%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 7.61-7.57 (m, 2H), 7.49 (s, 1H), 7.43-7.38 (m, 2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.86 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)=[O:7])C.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].Cl>CCCCCC.O1CCCC1>[CH2:19]([O:18][C:15](=[O:17])[CH2:16][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:20]
Reactant: CCOC(=O)c1cc(Cl)ccn1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1cc(Cl)ccn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
Under a nitrogen atmosphere, 4 g (approximately 60% dispersion in paraffin oil, about 100 mmol) of sodium hydride are washed twice with 60 ml of n-hexane each time, and then 400 ml of absolute tetrahydrofuran are added. The mixture is heated to 50° C. and, in the course of 2 hours, a solution of 13.36 g (72 mmol) of 4-chloropyridine-2-carboxylic acid ethyl ester and 10.04 g (114 mmol) of ethyl acetate in 60 ml of absolute tetrahydrofuran is added dropwise, during which the mixture begins to boil vigorously. When the exothermic reaction has subsided, stirring is carried out for 12 hours at room temperature to complete the reaction. The yellow suspension is poured into 400 ml of ice-water and rendered neutral with 15% hydrochloric acid, and the solution is concentrated to half its volume. Extraction is then carried out twice with 200 ml of ethyl acetate each time, and the organic extracts are combined, dried (sodium sulfate), filtered and concentrated. 14.5 g of 3-(4-chloropyrid-2-yl)-3-oxopropionic acid ethyl ester are obtained in the form of a light-brown oil, which is used for further syntheses without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:11]1[N:12]=[C:13]([NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:14][CH:15]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cc(Cl)c(-c2csc(N)n2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2csc(NC(=O)c3ccncc3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of 4-(2,6-dichloro-4-methoxyphenyl)thiazol-2-ylamine (10-5, 0.10 g, 0.36 mmol) in CH2Cl2 (10 mL) was added DMAP (88 mg, 0.72 mmol) followed by isonicotinoyl chloride hydrochloride (83 mg, 0.47 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-(4-(2,6-dichloro-4-methoxyphenyl)thiazol-2-yl)isonicotinamide (50 mg, 0.13 mmol) as white solids in 37% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J=5.8 Hz, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.31 (d, J=1.7 Hz, 1 H), 7.26 (s, 1 H), 7.22 (d, J=1.7 Hz, 1 H), 3.75 (s, 3 H). ESI-MS: m/z 381.4 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([F:30])=[C:26](I)[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[C:36]1[O:40][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][CH:37]=1>>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([F:30])=[C:26]([C:39]5[O:40][C:36]([CH:32]6[O:33][CH2:34][CH2:35][O:31]6)=[CH:37][CH:38]=5)[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Product: Fc1cc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2cc1-c1ccc(C2OCCO2)o1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.89 (d, 1H), 8.46 (s, 1H), 8.1 (d, 2H), 7.69 (d, 1H), 7.61 (m, 2H), 7.26 (m, 5H), 6.96 (m, 1H), 6.74 (d, 1H), 6.01 (s, 1H), 5.65 (s, 2H), 4.09 (m, 2H), 3.96 (m, 2H). ESI-MS m/z 506 (M−1).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CN1CCCNCC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2CCCN(C)CC2)cc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 24.1 %

Procedure:
1-Methyl-1,4-diazepane (15.07 g, 132.00 mmol) was added to methyl 4-fluorobenzoate (7.76 mL, 60 mmol) in DMA (150 mL). The resulting solution was stirred at 100° C. for 40 h. The reaction mixture was evaporated and quenched with 2M sodium hydroxide (50 ml). This was extracted with DCM (3×50 ml). The combined organic extracts were washed with saturated brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (3.59 g, 24.10%) as a tan waxy solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]=2[C:10]=1[Li].[CH3:16][Si:17]([CH3:20])(Cl)[Cl:18]>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]=2[C:10]=1[Si:17]([CH3:20])([CH3:16])[Cl:18]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1=C(C)Cc2ccc3ccccc3c21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C([Si](C)(C)Cl)c2c(ccc3ccccc23)C1
Temperature: 0 °C
Yield: 100 %

Procedure:
The thus-obtained white solid (2-methylbenzo[e]indenyllithium, 0.94 g, 5.1 mmols) was dissolved in dry tetrahydrofuran/diethyl ether (40 ml, 1/1 v/v). On the other hand, dimethyldichlorosilane (2.60 g, 20.2 mmols) was dissolved in dry tetrahydrofuran/diethyl ether (20 ml, 1/1 v/v), and the resulting solution was dropwise added to the previously-prepared 2-methylbenzo[e]indenyllithium solution at −5° C., over 1 hour. After the addition, this was immediately warmed up to 0° C. with stirring, and further stirred at room temperature for 2 hours. The solvent was removed from the pale yellow suspension under reduced pressure to obtain a yellow paste. The paste was extracted with dry diethyl ether (10 ml×3), and the resulting solution was filtered through a cannula. The filtrate was collected, the solvent was removed under reduced pressure, and this was dried under reduced pressure until it had a constant weight. The thus-obtained viscous yellow oil is 2-methylbenzo[e]indenyldimethylchorosilane (1.35 g, yield 100%).