Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.COC(=O)C1C=CC(N)=C([C:87]([F:90])([F:89])[F:88])C=1>N1C=CC=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([C:87]([F:90])([F:89])[F:88])[CH:10]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1
Yield: 74 %

Procedure:
This compound was synthesized in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), 4-amino-3-trifluoromethyl-benzoic acid methyl ester and using pyridine as a base to afford the title compound as a colorless solid (74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18](Br)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34]1([CH2:40][C:41]#[CH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.[Cu]I.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>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:42]#[C:41][CH2:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ccc3cc2=O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ccc3cc2=O)cc1
Temperature: 65 °C

Procedure:
A solution of 4-(7-bromo-3-oxo-2H-isoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (1.50 g, 3.62 mmol) in dimethylformamide (10 mL) is degassed with nitrogen, then treated with triethyl-amine (2.07 mL, 14.8 mmol), CuI (0.050 g, 0.26 mmol), Pd(Ph3P)4 (0.173 g, 0.15 mmol), and 3-phenyl-1-propyne (1.13 mL, 9.05 mmol). The reaction mixture is heated in an oil bath at 65° C. for 5 hours, cooled to room temperature, the DMF is evaporated, and the residue is dissolved in ethyl acetate. The solution is washed with 1N HCl, brine, dried over MgSO4 and evaporated onto silica gel. Purification on a 3.5×18 cm silica gel column eluted with hexane/ethyl acetate 4:1, followed by drying, will afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.ClC1C=CC(C(O)=O)=C(OC)C=1.S(Cl)(Cl)=O.Cl.Cl.[NH2:31][C:32]1[C:37]([NH2:38])=[CH:36][N:35]=[CH:34][N:33]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:31][C:32]1[C:37]([NH:38][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[O:11][CH3:12])=[CH:36][N:35]=[CH:34][N:33]=1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: Nc1cncnc1N
Agent: CN(C)c1ccncc1
Agent: COc1cc(Cl)ccc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1cc(Cl)ccc1C(=O)Nc1cncnc1N
Reaction time: 2 h

Procedure:
The 4-chloro-2-methoxy-benzoyl chloride prepared from 5.6 g of 4-chloro-2-methoxy-benzoic acid and 100 ml of thionyl chloride was dissolved as crude product in 100 ml of pyridine and mixed successively with 5 g of 4,5-diaminopyrimidine dihydrochloride and 1 g of 4-dimethylamino pyridine. After stirring for at first 2 hours at room termperature and then for 1.5 hours at 100° C., the reaction mixture was evaporated to dryness, mixed with water, and neutralized with sodium bicarbonate. The precipitate obtained was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH3:65])[CH2:45]2)[CH:7]([CH3:67])[CH2:6][CH2:5][C:4]1=[O:68])[CH3:2].[N-:69]=[N+:70]=[N-:71].[Na+].O>CN(C=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:69]=[N+:70]=[N-:71])[CH:46]([O:63][CH2:64][CH3:65])[CH2:45]2)[CH:7]([CH3:67])[CH2:6][CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 80 °C

Procedure:
To a stirred solution of 17-ethyl-1-hydroxy-12-[2'-[4"-(2"'-nitrobenzenesulfonyloxy)-3"-ethoxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (87 mg, Example 47) in dry DMF (1 ml) is added sodium azide (16.7 mg) in one portion. The reaction is heated at 80° C. under nitrogen atmosphere for 3 h. The reaction mixture is cooled, poured into water (5 ml) and extracted with ethyl acetate. Normal work-up followed by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [C:1](OCC)(=O)[CH:2]=C.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1.C(OCC=C)(=O)C=C.N(C(C)(C)C#N)=NC(C)(C)C#N.B(F)(F)F.C=C>CC(C)=O.C(Cl)Cl>[CH2:1]=[CH2:2].[C:11]([O:13][CH:8]=[CH2:9])(=[O:12])[CH3:10].[C:11]1(=[O:12])[O:13][C:8](=[O:14])[CH:9]=[CH:10]1
Reactant: C=CC(=O)OCC
Agent: C=C
Agent: C=CCOC(=O)C=C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(C)=O
Solvent: ClCCl
Product: C=COC(C)=O

Procedure:
A 7.57-liter stirred autoclave was charged under nitrogen with 4000 ml. of methylene chloride, 400 grams of ethyl acrylate, 20 grams of maleic anhydride, 1.2 grams of allyl acrylate, and 1.0 gram of azobis(isobutyronitrile). It was then sealed, charged with 300 grams of boron trifluoride, and pressured to 21 kg./sq. cm. with ethylene. The subsequent copolymerization at 25° C. was continued until pressure measurement indicated that ethylene uptake had ceased (about two hours later). The reaction was quenched by addition of 1 liter of diethyl ether. Volatiles were removed by steam-stripping in a well-ventilated hood. The terpolymer thereby obtained was dissolved in acetone, precipitated in water in a blender, and oven-dried. Yield: 415 grams.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](Cl)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(CCc2sccc2S(=O)(=O)Cl)cc1
Product: Cc1ccc(CCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 52 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide was prepared, as described in Example 10, using 2-[(4-methyl)phenethyl]thiophene-3-sulfonyl chloride and 5-amino-4-bromo-3-methylisoxazole in 52% yield.
Reaction SMILES: [O:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH:9](O)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[N:39]=[C:38]([SH:44])[N:37]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[O:1]([C:8]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH:9]([S:44][C:38]1[N:37]=[C:36]([O:35][CH3:34])[CH:41]=[C:40]([O:42][CH3:43])[N:39]=1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(C)(Oc1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
7.2 g (25 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (comp. 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in 100 ml of DMF and added dropwise to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 nm mmol) of sodium bicarbonate in 100 ml of DMF at 0° C. After stirring at room temperature for 2 hours and at 60° C. for a further 2 hours, the mixture is poured into 1 1 of ice-water, and the precipitate is filtered off with suction. Drying results in 4.2 g of a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=O)=[C:7]([O:17][CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:14]([CH3:15])[CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(C)(C)C)ccc1CC(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)ccc1CCN(C)C
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 0.323 g (0.13 mmol) of the product of Step C in 10 mL of anhydrous THF was carefully added 0.1 g (2.63 mmol) of lithium aluminum hydride. The reaction mixture was then stirred overnight under a nitrogen atmosphere at 65° C. The reaction mixture was then cooled using an external ice water bath, 5.0 mL EtOAc was added. The reaction mixture was stirred an additional 20 min, at which point an excess of 2.5 N aqueous sodium hydroxide was added, followed by 50 mL EtOAc. The aqueous layer was separated and re-extracted with EtOAc. The organic layers were combined, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:30])[C@@H:7]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:30])[C@@H:7]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)OCC(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3c (2.2 g, 1.0 eq) and EtOH (11 mL) at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (304.1 mg, 0.8 equiv) in H2O (4 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed complete as determined by TLC. 1N HCl aqueous solution (32 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (200 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4c. The diastereomeric ratio of crude 4c was determined to be 64/36 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4c (2.20 g, 83% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].CN1C=CN=C1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:27][CH2:26][C:28](=[O:29])[CH3:30])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C=CC(C)=O
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Agent: Cn1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 70 °C
Reaction time: 11 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (600 mg, 1.69 mmol) and methyl vinyl ketone (0.42 ml, 5.18 mmol) were added to a solution of 1-methylimidazole (7 μl, 0.085 mmol) in DMSO (6 ml). The reaction mixture was stirred at 70° C. for 11 h. Then water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-98:2) to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.21 (3H, d), 2.16 (3H, s), 2.92 (2H, t), 4.26 (2H, t), 4.28 (1H, distorted dd), 4.39 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (1H, d), 7.50 (1H, d), 7.52 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@@H:11]1[CH2:19][OH:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Cl)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@@H:11]1[CH2:19][O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C[C@@H]2[C@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 2 (2.40 g, 8.8 mmol), 4-(dimethylamino)pyridine (100 mg, 0.82 mmol), and imidazole (1.00 g, 14.7 mmol) in methylene chloride (35 mL) was added dropwise t-butyldiphenylchlorosilane (2.85 g, 10.4 mmol). After stirring overnight, the mixture was added to saturated ammonium chloride (40 mL), extracted with ethyl acetate (3×40 mL), dried (magnesium sulfate), filtered, concentrated, and chromatographed on a 14 cm tall×53 mm diameter silica gel eluting with 30% ethyl acetate in hexane to afford 3 (3.776 g, 83%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[Sn:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].O[N:43]1[C:47](=[O:48])[CH2:46][CH2:45][C:44]1=[O:49].CCN=C=NCCCN(C)C>C(#N)C>[F:41][C:2]([F:1])([F:40])[C:3]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[Sn:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][N:43]1[C:47](=[O:48])[CH2:46][CH2:45][C:44]1=[O:49])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC(=O)CCC(=O)ON2C(=O)CCC2=O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Compound 9 (66 mg, 93 μmol) was dissolved in acetonitrile (2 mL), N-hydroxysuccinimide (21.5 mg, 187 μmol) and EDCI (36 mg, 187 μmol) were added and the mixture stirred at 20° C. overnight. The solvent was removed under vacuum and the residue was purified over silica gel using dichloromethane/AcOEt (4/1) as eluant to give 45 mg (93 μmol, 60% yield) of a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCCN1CCN(c2cc(C3CC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2.9 g of 2-tert-Butyl-4-piperazin-1-yl-6-cyclopropyl-pyrimidine (11.1 mmol), 1.8 g acetic acid 3-chloro-propyl ester (13.2 mmol), 1.38 g of triethylamine (13.7 mmol), and a spatula tip of sodium iodide were dissolved in 50 ml of dimethylformamide and stirred for 8 h at 80° C. After cooling to room temperature, the dimethylformamide was evaporated. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product (3.7 g) was directly used in the subsequent reaction step.
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N.[H][H]>[Ni]>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 125 °C
Yield: 172.5 %

Procedure:
An autoclave was charged with 0.42 mol 100 g 5-phenyl-5-methylnonanedinitrile, 10 g Raney nickel, and 9.86 mol 400 mL methanol. The reaction mixture was flushed with nitrogen and then charged with 8.9 mol 150 g ammonia. The reactor was then pressurized to 1500 psig with hydrogen and heated at 125° C. for two hours. The reactor was cooled, vented, the contents filtered, and the filtrate concentrated in a rotary evaporator. Another hydrogenation run was made under essentially the same conditions described above except that 0.46 mol 110 g of 5-phenyl-5-methylnonanedinitrile was employed. The product of this run was concentrated as described above. Analysis of these concentrates by NMR and GLC indicated that complete hydrogenation of the nitrile groups to amino groups had been accomplished. The concentrates were then fractionally distilled under vacuum to give 180 g of 5-phenyl-5-methyl-1.9-nonanediamine for an 84 mol percent yield based on the 5-phenyl-5-methylnonanedinitrile.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][OH:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:34](N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][O:12][CH3:34])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(NC(=O)Nc2ccc(-c3c(CO)cn4ncnc(N)c34)cc2)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of DCM (5 mL) was added N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(4-methylpyridin-2-yl)urea (Example 262) (40 mg, 0.10 mmol) followed by 2M thionyl chloride in DCM (0.51 mL, 1.03 mmol). The solution was stirred at rt for 1 h and was then evaporated in vacuo. THF (5 mL) and MeOH (5 mL) were added to the crude reaction followed by triethylamine (43 μL, 0.31 mmol). The solution was heated to 50° C. for 3 d and then evaporated in vacuo and purified by MPLC (Isco) 0-5% MeOH/DCM. The resulting purified fractions were combined and evaporated producing 25 mg of the title compound (0.061 mmol, yield 60%). 1H-NMR (DMSO-d6) δ 10.86 (s, 1H), 9.46 (s, 1H), 8.14 to 8.13 (d, J=6.3 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.65 to 7.63 (d, J=8.7 Hz, 2H), 7.36 to 7.34 (d, J=8.6 Hz, 2H), 7.27 (s, 1H), 6.87 to 6.86 (d, J=5.0 Hz, 1H), 4.27 (s, 2H), 3.20 (s, 3H), 2.30 (s, 3H); MS [M+H]+=404.0; LCMS RT=1.99 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH2:17][CH3:18])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([OH:22])=[O:21])[C:3]=1[Cl:23].[OH-].[Na+].[NH2:26][C:27]1[C:32]([F:33])=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH2:42][CH3:43])[C:35]=2[F:44])[N:30]=[C:29]([C:45]([O:47]C)=[O:46])[C:28]=1[Cl:49].Cl>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH2:17][CH3:18])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH2:31][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:21])[C:3]=1[Cl:23].[NH2:26][C:27]1[C:32]([F:33])=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH2:42][CH3:43])[C:35]=2[F:44])[N:30]=[C:29]([C:45]([OH:47])=[O:46])[C:28]=1[Cl:49]
Reactant: CCOc1c(Cl)ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)c1F
Agent: CCOc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 23 °C
Reaction time: 4 h

Procedure:
4-Amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinic acid. A 2 M solution of aqueous NaOH (900 μL, 1.8 mmol, 4.0 equiv) was added to a stirred suspension of methyl 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinate (170 mg, 0.45 mmol, 1.0 equiv) in methyl alcohol (3.0 mL) at 23° C. The resulting heterogeneous white mixture was stirred at 23° C. for 4 h. The reaction mixture was adjusted to approximately pH=4 via dropwise addition of concentrated HCl and then concentrated via rotary evaporation. The residue was slurried in water and vacuum filtered to afford the desired product, 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinic acid as a white powder (140 mg, 88%): mp 163-165° C.; IR (thin film) 3486 (m), 3377 (s), 3155 (w), 2981 (w), 2935 (w), 1718 (s), 1614 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 7.45 (dd, J=9, 2 Hz, 1H), 7.28 (dd, J=9, 7 Hz, 1H), 7.01 (br s, 2H), 4.15 (q, J=7 Hz, 2H), 1.33 (t, J=7 Hz, 3H); ESIMS m/z 363 ([M+H]+).