Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCCCCC>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC(Cl)(Cl)Cl

Procedure:
L-phenylalanine was reacted with 2,2,2-trichloroethyl chloroformate in a 2N sodium bicarbonate solution, and after the usual working-up there was obtained the desired acid as crystals, melting point 126° (from methylene chloride/hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27])(=[O:23])=[O:22].FC(F)(F)C(O)=O.CC(O)C>Cl>[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[CH3:31])(=[O:22])=[O:23]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C#CCOc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (VI-53) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:33])[CH2:16][NH:17][C:18]([CH2:20][N:21]([CH2:29][C:30](O)=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:59][O:60][C:61](=[O:67])[C@@H:62]([CH:64]([CH3:66])[CH3:65])[NH2:63]>CN(C)C=O>[CH3:59][O:60][C:61](=[O:67])[CH:62]([NH:63][C:30](=[O:31])[CH2:29][N:21]([CH2:20][C:18](=[O:19])[NH:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:33])[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH:64]([CH3:66])[CH3:65]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(C)C
Yield: 87.1 %

Procedure:
4-Methylmorpholine (4.1 mL, 37.3 mmol) was added to a suspension of ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol), and HATU (4.61 g, 12.1 mmol) in dimethylformamide (25 mL). After 5 minutes d-valine methyl ester hydrochloride (1.56 g, 9.3 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2×100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid methyl ester (4.37 g, 8.1 mmol, 87%). C23H32BrN3O7 calculated 541.1 observed [M+1]+431.1; rt=2.65 min.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[NH:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:13]=3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:27](=O)([O-])O.[Na+]>CO>[C:5]1([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[NH:21][N:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:13]=3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reaction time: 0.5 h

Procedure:
18 μL of thionyl chloride were initially introduced into 0.5 ml of methanol and the mixture was stirred for 30 min. 19 mg of 5-phenyl-1H-pyrazolo[4,3-c]isoquinoline-3-carboxylic acid (60) in 0.5 ml of methanol were then added dropwise. The mixture was stirred at RT for 12 h, after which a saturated solution of sodium hydrogen carbonate was added and the whole was extracted, in each case 1×, with ethyl acetate and methylene chloride. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 61. C18H13N3O2 (303.32) MS (ESI) 304 (M+H)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])(O)=O.[Na+]>CC(C)=O.O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Cyanuric chloride (2.22 g, 12.0 mmol) in acetone (50 mL) was added to well-stirred ice water (72 mL). To the resulting fine slurry at 0° C. was slowly added a solution of 1-Boc-piperazine (2.24 g, 12.0 mmol) in acetone (20 mL). A solution of NaHCO3 (1.0 g) in water (20 mL) was slowly added to the mixture, which was subsequently stirred at 0° C. for an additional 2.5 h. The resulting precipitate was collected by filtration, washed with water, and dried to yield a white solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:17]([CH3:16])[C@H:18]2[CH2:37][N:22]3[C:23]4[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]3[CH2:20][CH2:19]2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-fluoro-3-(trifluoromethyl)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 463.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)C(OCOC(=O)CC)=O)(=O)C.[C:36](Cl)(=[O:47])[O:37][CH2:38][O:39][C:40](=[O:46])[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43]>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:29][CH2:28][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:36]([O:37][CH2:38][O:39][C:40](=[O:46])[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:47])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:32][CH2:31]1
Reactant: CC(C)(C)CC(=O)OCOC(=O)Cl
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Solvent: ClCCl
Product: CC(C)(C)CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 46 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (589.0 mg, 1.72 mmol) in dichloromethane (14 mL) and 3,3-dimethyl-butyroxymethyl carbonochloridate (7 g) gave the titled product in 46% yield (407.2 mg, 0.79 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.24 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.26 (t, 1H), 4.75-4.82 (m, 1H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.68 (ddd, 1H), 3.56 (dt, 1H), 3.13-3.19 (m, 4H), 3.10 (dt, 1H), 2.35-2.46 (m, 2H), 2.16-2.25(m, 4H), 1.00 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CS(C)=O>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5]([C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)[CH:3]=3)=[O:6])=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCC(O)CC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-hydroxypiperidine in DMF. [α]D20=+16.1° (c=0.35, DMSO), ES-MS m/e (%): 471 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.Cl.[CH2:21]([N:23]1[CH2:27][CH2:26][C:25]2([CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:24]1)[CH3:22]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:30][CH2:31][C:25]4([CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]4)[CH2:28]3)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCN1CCC2(CCNC2)C1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Product: CCN1CCC2(CCN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4CC)C2)C1

Procedure:
The title compound was prepared according to example 24 by reacting 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 2-ethyl-2,7diazaspiro[4.4]nonane dihydrochloride; mp 215°-217° C. (dec).
Reaction SMILES: C(Cl)(Cl)Cl.[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18](=[O:20])[C:17]([C:21](=O)[CH2:22][CH3:23])=[C:16]([OH:25])[CH2:15]2)=[CH:10][CH:9]=1)=[O:6].[CH2:26]([O:28][NH2:29])[CH3:27]>C(O)C>[CH2:26]([O:28][N:29]=[C:21]([C:17]1[C:18](=[O:20])[CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH:5]=[O:6])=[CH:9][CH:10]=2)[CH2:15][C:16]=1[OH:25])[CH2:22][CH3:23])[CH3:27]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC=O)cc2)CC1=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC=O)cc2)CC1=O
Reaction time: 3 h
Yield: 66.9 %

Procedure:
Into 25 ml of chloroform was dissolved 1.3 g of 5-(4-formamidophenyl)-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 1.0 g of ethoxyamine and 5 ml og ethanol. The mixture was kept for 3 hours in a water bath having 40° C. and the reacting solution was washed with a dilute hydrochoric acid solution and water. The solution was extracted with 15 ml of aqueous solution containing 5% of sodium hydroxide and to the alkaline solution was added a dilute hydrochloric acid solution and the crystal sedimented was extracted with chloroform. The solution was washed with water and to the solution was added anhydrous magnesium sulfate and a small amount of active carbon. And then, the mixture was agitated and filtered and the filtrate solution was concentrated. Ethyl ether was added in the residue and the crystal sedimented was collected with a filtering step and 1.0 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 111°-113.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:22])[C:8]1[C:13]([C:14]2([Cl:21])[CH2:18][C:17]([F:19])=[C:16]([NH2:20])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Ca+2].[C:28](Cl)(Cl)=[S:29].C(=O)=O>ClCCl.O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:22])[C:8]1[C:13]([C:14]2([Cl:21])[CH2:18][C:17]([F:19])=[C:16]([N:20]=[C:28]=[S:29])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N)S1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N=C=S)S1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.8 g of the 5-amino-2-chloro-4-fluoro-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P2 in 100 ml of dichloromethane is added dropwise at 25°-30° C. to a suspension of 6 g of calcium carbonate, 4 ml of thiophosgene, 20 ml of dichloromethane and 20 ml of water. After the evolution of carbon dioxide has ceased, the mixture is stirred for 18 hours at room temperature. After filtration and washing with water, the organic phase is separated off, dried over sodium sulfate and then concentrated by evaporation, yielding 4.8 g of 2-chloro-4-fluoro-5-isothiocyanato-thiolbenzoic acid (methoxycarbonylmethyl) ester in the form of an oil which is used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Methyl 4-methylsalicylate (98.1 g, 590 mmoles) was dissolved in carbon tetrachloride (600 mL), and N-bromosuccinimide (105.0 g, 590 mmoles) and benzoyl peroxide (0.7 g, 3 mmoles) were added. The mixture was refluxed under nitrogen. After 2 hours, an additional portion (0.7 g) of N-bromosuccinimide was added. Reflux was continued for 16 hours. The reaction mixture was cooled to room temperature and the solid removed by filtration. The yellow filtrate was evaporated to dryness to afford a thick yellow syrup that solidified on standing. Hexanes (500 mL) was added to the solid, and the mixture was boiled until almost all solids dissolved. The hot hexanes solution was filtered and concentrated until a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. Pale yellow crystals formed slowly. The mixture was then chilled in ice for 2 hours to complete crystallization. Finally, the solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 83.5 g (58% yield) of methyl 4-bromomethyl-salicylate (m.p. 73°-75° C., open capillary, uncorrected).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CC[N:34](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH2:34])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (24 μL, 0.14 mmol) and PyBOP® (40 mg, 0.077 mmol). After stirring the mixture at RT for 15 minutes, ammonia was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by ammonia bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide. (27 mg, 0.066 mol, 47%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:19][CH:18]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>ClCCl.C1(C)C=CC=CC=1>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])=[CH:21][CH:22]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Stir a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.75 g, 9 mmol), 3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (2.9 g, 9 mmol), toluene (10 mL), and dichloromethane (10 mL) at −20° C. Add 1,1′-(azodicarbonyl)dipiperidine (4.5 g, 18 mmol) followed by tributylphosphine (4.5 mL, 18 mmol) and allow the resulting yellow solution to stir at room temperature overnight. Concentrate the resulting thick reaction mixture and dilute with ether (50 mL). Cool the slurry to 0° C. with stirring, for 30 minutes. Filter the reaction mixture, concentrate, and purify via silica chromatography eluting with 1:1 hexanes:(5:4:1 hexanes:dichloromethane:ethyl acetate) to give the title compound (3 g, 67%), as an orange thick oil. LCMS (m/z) 498 M−1.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)C(C)C(OC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N>>[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C(C)C(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)C(C)C(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: COC(=O)C(C)C(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-3-methoxy-2-methyl-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-3-methoxy-2-methyl-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a single diastereomer (diastereomer B, tr=18.7 min from Example 147-A) following the procedure shown in Example 142-C. MS (ESI+) m/z 403.0 (M+H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: NC(=O)CCC(=O)O
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CCC(=O)OCc1ccccc1

Procedure:
A mixture of 23.4 g. (0.20 mole) of succinamic acid, 25.4 g. (0.20 mole) of benzyl chloride, 20.2 g. (0.20 mole) triethylamine and 250 ml. dimethylformamide is stirred at 95° C. for 20 hours. The reaction mixture is diluted with 500 ml. water the product extracted into two 200 ml. portions of ethyl ether. The combined ether extracts are washed with two 50 ml. portions of saturated sodium bicarbonate solution, then two 50 ml. portions of water and dried over anhydrous magnesium sulfate. After filtering, the solution is concentrated at 15 - 20 mm. and 40° C. to give benzyl succinamate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:8]=2)[CH:2]=1.O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)[N:8]=2)[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Temperature: 90 °C

Procedure:
To a solution of 2-[2-pyridin-3-yl-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-isoindole-1,3-dione (0.1 g, 0.217 mmol) in ethanol (5 mL) was added hydrazine mono-hydrate (14 μl, 0.434 mmol) at rt. The resulting mixture was heated to 90° C. for 12 h then cooled to rt. The resulting mixture was concentrated and taken on crude to the next step. MS (ESI): mass calcd. for C17H13F3N4, 330.1; m/z found, 331.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]([NH2:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(O)C>[C:10]([NH:13][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)N
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)Nc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
251 mg of 4,6-dichloropyrimidine, 123 mg of 2-methylpropan-2-amine and 260 mg of DIPEA were dissolved in 2.5 mL of i-PrOH and charged into a screw cap vial and the vial obtained was kept overnight in a heating block at 90° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., solvent was evaporated and pure N-tert-butyl-6-chloropyrimidin-4-amine was obtained by column chromatography using PE:EtOAc 10:1.
Reaction SMILES: Cl[C:2]1[C:3]([OH:21])=[CH:4][C:5]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:10][N:9]([CH3:19])[CH2:8][CH2:7][C:6]=2[CH:20]=1.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]1[C:5]2[CH:4]=[C:3]([OH:21])[CH:2]=[CH:20][C:6]=2[CH2:7][CH2:8][N:9]([CH3:19])[CH2:10]1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2ccccc2F)C1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2ccc(O)cc2C(c2ccccc2F)C1
Temperature: 60 °C
Yield: 89 %

Procedure:
10.0 g 8-chloro-5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 500 ml acetic acid containing sodium acetate. Palladium-on-carbon was added and the suspension was heated to 60° C. Under vigorous stirring hydrogen was led through the suspension giving after 48 h 7,9 g crystalline compound. Yield 72%.