Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[CH2:23][NH:24][CH:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1)[CH3:2].[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:43]=2[S:44][C:45]=1[C:46](Cl)=[O:47]>>[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:43]=2[S:44][C:45]=1[C:46]([N:24]([CH2:23][C:5]1[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:27][CH2:26]1)=[O:47]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: CCOc1ccc(-c2ccc(C(O)(O)C(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 119 (487 mg, 0.88 mmol) is treated with acid chloride 8 (235 mg, 0.88 mmol) using Method D to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.C(NC(C)C)(C)C.C([Li])CCC.ClP(=O)(OCC)[O:31][CH2:32][CH3:33]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)=[CH:33][CH:32]=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1cccc(F)c1)c1cccc(F)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=CC=C(c1cccc(F)c1)c1cccc(F)c1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 3,3'-difluorobenzophenone (19.8 g), diisopropylamine (32.2 mL), 1.55M n-butyl lithium in hexane (148 mL), acetaldehyde N-tertbutylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up gave 23 g of material which was crystallized from hexane to give 17.4 g of 3,3-bis(3-fluorophenyl)-2-propenal, mp 51°-53° C. A small portion was recrystallized from the same solvent to provide the analytical sample, mp 52°-54° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[CH:9]1([C:15]2[CH:16]=[C:17]([CH2:28][CH2:29][C:30](OC)=[O:31])[CH:18]=[C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:20]=2[OH:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:34](=[O:37])(O)[O-].[Na+]>C(O)(=O)C>[CH:22]1([C:19]2[CH:18]=[C:17]([CH2:28][CH2:29][C:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:34](=[O:37])[CH2:29][CH2:28][C:17]3[CH:18]=[C:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:20]([OH:21])=[C:15]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:16]=3)=[O:31])[CH:16]=[C:15]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:20]=2[OH:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1
Reactant: O=C([O-])O
Reactant: NCCCCCCN
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1)NCCCCCCNC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1
Temperature: 175 °C
Reaction time: 1 h

Procedure:
11.6 of 1,6-diaminohexane are heated, under nitrogen, to 175° C. Then 0.2 g of acetic acid are added. Over 1 hour, 68.9 g of methyl 3-(3,5-dicyclohexyl-4-hydroxyphenyl)propionate are added to this mixture. The reaction mixture is heated for a further 3 hours at 175° C. The mixture is stirred, in a mixer, with 100 ml of 1% aqueous sodium bicarbonate. The resultant solid is isolated by suction filtration and washed with water until neutral. After drying, 60.3 g of a colourless powder with a melting point of 28° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1.CSC.[B].C1COCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:35].Cl>>[ClH:35].[ClH:35].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][NH2:1])=[CH:6][C:7]=1[F:13]
Reactant: N#Cc1ccc(CCCN)cc1F
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [B]
Solvent: C1CCOC1
Solvent: CSC
Product: NCCCc1ccc(CN)c(F)c1
Yield: 73 %

Procedure:
Scheme IIIb, step C: 4-(3-Aminopropyl)-2-fluorobenzenecarbonitrile (1.1 g, 6.17 mmol) and boron dimethylsulfide 2M in THF (6.2 mL, 12.34 mmol) were combined and reduction was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, 3-[4-(aminomethyl)-3-fluorophenyl]propylamine dihydrochlorde, (1.15 g, 73%) as a dihydrochloride salt. Electron spray M.S. 183 (M*+H).
Reaction SMILES: ClC1C=CC=CC=1C1C=CC(C(=O)C)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[H][H]>C1C=CC=CC=1>[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)[CH3:31]
Reactant: [H][H]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(=O)c1ccc(-c2ccccc2Cl)cc1
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 7 h

Procedure:
The procedure of Example 3 was repeated, except that the 4'-(2-chlorophenyl)acetophenone was replaced with an equal amount of 4'-(4-chlorophenyl)acetophenone, the amount of benzene employed was increased to 200 ml, and the amount of sulfuric was reduced to 5 drops. After seven hours, hydrogen pressure had dropped to 35.5 psig. Evaporation of the benzene left a solid which, according to nuclear magnetic resonance analysis, contained only about 67 percent of the desired ethylbenzene. Consequently, the solid was subjected to the hydrogenation procedure again, using 200 ml of benzene, 2 g of catalyst, and 1 ml of concentrated sulfuric acid. The solid obtained upon evaporation of the benzene was recrystallized from hexane, giving 1-ethyl-4-(4-chlorophenyl)benzene, mp 103°-127 104°. The following elemental analysis was obtained:
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([C@H:20]2[CH2:22][O:21]2)[N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([NH:27][C:28]([C@@H:30]1[CH2:39][C@H:38]2[C@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][NH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[C:23]([NH:27][C:28]([C@@H:30]1[CH2:39][C@H:38]2[C@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][N:31]1[CH2:22][C@@H:20]([OH:21])[C@@H:8]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A stirred solution of 4.39 g (15 mmol) of 2(S)-[2-phenyl-1(S)-phthalimidoethyl]oxirane and 3.57 g (15 mmol) of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 30 ml of dimethylformamide was heated at 120° C. for 10 hours and then left to stand at room temperature for 18 hours. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, washed with 30 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated. The crude product was crystallized from ethyl acetate/n-hexane and there were obtained 4.77 g of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide in the form of a cream coloured solid; MS: m/e 532 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][C:15]([NH2:17])=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[O:19][C:20](=O)/[C:21](/[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[C:22](\O)/[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[C:26]([O:25][C:23]([C:22]1[C:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:20]([OH:19])[N:17]=[C:15]([CH2:14][C:9]2([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:16]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)CC1(c2ccc(Cl)cc2)CCCC1
Agent: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 55.1 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (27-02) (12 g, 55%) was synthesized from [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (26-02) (12 g, 44.03 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (23.49 g, 76.27 mmol) as a yellow solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(-c2ccc(OC)cc2)cc1[N+](=O)[O-]
Agent: Cl
Product: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1

Procedure:
Crude dimethyl 4′-methoxy-3-nitro-biphenyl-4-malonate was heated at 100° C. in 60 mL of 6N hydrochloric acid for 15 hours and cooled. The precipitate was collected by filtration, washed with water and hexane, and dried to give 7.2 g of crude 4′-methoxy-3-nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: [CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([OH:29])=O)=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.[NH:68]1[CH2:73][CH2:72][S:71](=[O:75])(=[O:74])[CH2:70][CH2:69]1>C(Cl)Cl.CN(C=O)C>[CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([N:68]5[CH2:73][CH2:72][S:71](=[O:75])(=[O:74])[CH2:70][CH2:69]5)=[O:29])=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=S1(=O)CCNCC1
Reactant: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)N1CCS(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a stirred solution of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylthiazole-5-carboxylic acid (example 69B, 33 mg, 0.067 mmol), HATU (50.8 mg, 0.134 mmol), 2,6-lutidine (0.020 mL, 0.174 mmol), and DMF (1 mL) was added thiomorpholine 1,1-dioxide (27.1 mg, 0.201 mmol). The solution was then stirred at 50° C. for 1.5 hrs. The reaction was then cooled to room temperature and diluted with methylene chloride. The solution was then washed with saturated aqueous sodium bicarbonate, 10% LiCl in H2O, and saturated aqueous sodium bicarbonate again. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude residue was then purified by silica-gel flash chromatography using an Isco 40 g column eluting from 0-6% MeOH/CH2Cl2 to give N,N-dicyclopropyl-6-ethyl-4-(4-ethyl-5-(1,1-dioxothiomorpholine-4-carbonyl)thiazol-2-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (21.7 mg, 52.6% yield) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH:10]([NH2:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH:13][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: CC(C)Nc1c(Cl)cnnc1Cl

Procedure:
A solution of 3,4,5-trichloropyridazine (9.2 g) and isopropylamine (16.5 g) in toluene (25 ml) is refluxed for 18 hr. Excess isopropylamine is removed by atmospheric distillation. The residual solution is cooled and diluted with dichloromethane and aqueous sodium hydroxide solution (5%). The phases are separated. The organic phase is washed with water and then with saline. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give a liquid which containes a mixture of isomeric products. The isomers are separated by flash chromatography on silica gel eluting with ether/hexane (30/70). The appropriate fractions are pooled and concentrated to give the desired isomer, NMR (CDCl3) 1.33, 4.59, 4.87 and 8.60δ; CMR (CDCl3) 24.2, 46.4, 117.1, 139.3, 145.5 and 151.3δ.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2
Yield: 9 %

Procedure:
Reaction of 2-phenylquinazolin-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 20 (9% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.66 and 3.18 (2d, 6H), 2.85 and 3.09 (2t, 2H), 3.60 and 4.21 (2t, 2H), 4.50 and 5.09 (2s, 2H), 6.35 and 6.82 (2d, 1H), 6.96 and 7.15 (2d, 1H), 7.53-7.64 (m, 4H), 7.92-8.18 (m, 3H), 8.62-8.68 (m, 2H); MS (ESI) m/z 425 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.C1[CH2:30][O:29]CC1.C([Mg]Cl)(C)C.C([O:38]CC)C>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:4]=[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:2]([C:30]([OH:29])=[O:38])=[CH:7][N:6]=1
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: Fc1ccc(Oc2ncc(Br)c(Oc3ccc(F)cc3F)n2)c(F)c1
Agent: CC(C)[Mg]Cl
Product: O=C(O)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Temperature: 0 °C

Procedure:
5-Bromo-2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine (1.0 g, 2.41 mmol) was added to 30 mL of a 1:1 mixture of dry THF and diethyl ether. The mixture was cooled to 0° C. in an ice bath, and isopropyl magnesium chloride (1.45 mL of 2 M solution in diethyl ether, 2.41 mmol) was added dropwise to the stirring mixture. The reaction mixture was stirred at 0° C. for on hour, then dry CO2 was bubbled through the stirring reaction mixture for 45 minutes. The reaction mixture was stirred under CO2 atmosphere for another 30 minutes, then was concentrated under reduced pressure. The residue was taken up into a mixture of 30 mL water and 5 mL THF, and the mixture was acidified to pH=2 by dropwise addition of 10% aqueous HCl. The mixture was extracted wtih EtOAc and the organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give 950 mg of 2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine-5-carboxylic acid. MS(M+H)=381.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])[N:8]=1.CO.C[O:24][C:25]1[C:28](=O)[C:27](=O)[C:26]=1[O:31]C.[CH3:33][NH2:34]>C(O)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:28]2[C:25](=[O:24])[C:26](=[O:31])[C:27]=2[NH:34][CH3:33])[N:8]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNc1c(NCCSCc2nccc(NC(N)=NCC(F)(F)F)n2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethyl)thiomethylpyrimidine (0.31 g.), methanol (5 ml.) and 1,2-dimethoxycyclobutene-3,4-dione (0.14 g.) was stirred at room temperature for 18 hours. A 33% w/v solution of methylamine in ethanol (5 ml.) was added and the mixture left at room temperature for 18 hours and then evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 1-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl-methylthio]ethylamino)-2-methylamino cyclobutene-3,4-dione (0.16 g.) characterised as the hydrogen maleate, m.p. 178°-184° after recrystallisation from a mixture of methanol and acetonitrile.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:24])([F:23])[O:22][C:18]=3[CH:17]=2)=[S:14])=[O:11])[CH:7]=[C:6]([CH3:27])[N:5]=1.[CH3:28]I.O>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([CH3:27])[N:5]=1)[C:10]([NH:12][CH:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]2[O:20][C:21]([F:24])([F:23])[O:22][C:18]=2[CH:17]=1)[S:14][CH3:28])=[O:11]
Reactant: CI
Reactant: Cc1cc(C(=O)NC(=S)Nc2ccc3c(c2)OC(F)(F)O3)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(NC(=O)c1cc(C)nc(Cl)c1)Nc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH, 60% (2.2 g; 0.0550 mol) was stirred in THF (170 ml) on an ice bath under N2. Intermediate D1 (19.3 g; 0.500 mol) was then added and stirred for 1 hour at 0° C. CH3I (7.8 g; 0.0550 mol) was then added and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the THF was evaporated in vacuo. The precipitate was filtered off, washed with water and dried. Yield: 22.86 g of intermediate D2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([O:15][CH2:16][CH:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)=[C:33]([F:44])[CH:32]=1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:34]2[CH:35]=[CH:36][C:31]([C:9]3[C:10]([O:15][CH2:16][CH:17]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18]4)=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:32][C:33]=2[F:44])=[N:38][CH:39]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncccc2B2OC(C)(C)C(C)(C)O2)C1
Product: CC(C)(C)OC(=O)N1CCC(COc2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using tert-butyl 3-(((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)methyl)pyrrolidine-1-carboxylate and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C25H28FN5O3, 465.22; m/z found, 466.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.58 (m, 1H), 8.18-8.09 (m, 2H), 8.03-7.94 (m, 1H), 7.73-7.64 (m, 1H), 7.48-7.36 (m, 2H), 7.05-6.96 (m, 1H), 4.70 (s, 2H), 4.47-4.22 (m, 2H), 3.68-3.26 (m, 3H), 3.25-3.09 (m, 1H), 2.77-2.60 (m, 1H), 2.14-1.98 (m, 1H), 1.84-1.68 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)=[CH:35][CH:34]=1>>[CH3:32][NH:31][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:41])[NH:39][C:36]4[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=4)=[CH:7][CH:6]=3)[N:9]=2)=[CH:23][CH:24]=1)=[O:30]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 4 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 51 mg, 4% yield.
Reaction SMILES: O[C@:2]1([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][C:6](=[O:8])[C@H:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:3]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:26]([O:25][C@H:3]1[C@H:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:5]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6](=[O:8])[CH:7]=[C:2]1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C[C@](O)(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of (3S,4S,5S,2R)-5-hydroxy-5-[(phenylmethoxy)methyl]-2,3,4-tris(phenyl methoxy)cyclohexan-1-one (580.0 g, 1.051 mol) in anhydrous methylene chloride (3.6 L) was added trifluoroacetic anhydride (331.1 g, 222 mL, 1.577 mol) followed by addition of pyridine (149.7 g, 153 mL, 1.892 mol) at room temperature under argon. The mixture was stirred at room temperature for 24 h and quenched by addition of ice water (1.0 L). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×2 L). The combined organic layers were washed with sodium bicarbonate (sat. aq. 3×0.5 L), brine (sat. aq. 3×1.0 L), dried over sodium sulfate, filtered and concentrated to give a yellow oil (476.7 g, purity of 90%, yield 85%). 1H NMR (CDCl3, 400 MHz): δ 7.26-7.48 (m, 20H), 6.26 (s, 1H), 5.15 (d, J=11.2 Hz, 1H), 5.05 (d, J=10.8 Hz, 1H), 4.95 (d, J=10.8 Hz, 1H), 4.77-4.81 (m, 2H), 4.72 (d, J=11.2 Hz), 4.55 (S, 2H), 4.40-4.42 (m, 1H), 4.31 (d, J=16 Hz, 1H), 4.03-4.13 (m, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:20]2)[CH:25]=1)=[O:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Ic1cccnc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccnc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 3-iodopyridine and N-(3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.