Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH3:25])[CH2:18][CH2:17][C:16]2[N:15]=[CH:14][C:13]([C:19]([O:21]CC)=O)=[C:12](Cl)[C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>C(O)CCC>[CH2:1]([O:8][C:9]1([CH3:25])[CH2:10][CH2:11][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:21])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[N:34]=[C:12]3[C:17]=2[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Solvent: CCCCO
Product: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
A solution of ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate (5.0 g) and p-chlorophenylhydrazine (2.0 g) in 75 mL of n-butanol is stirred at room temperature for 4 hours, then refluxed overnight. The reaction mixture is evaporated and the residue is treated with Et2O and 2N NaOH. The alkaline layer is separated, the pH is adjusted at 8 with dilute HCl, and the resulting precipitate is collected. This material is washed with EtH/Et2O and air-dried to obtain 8-benzyloxy-2-p-chlorophenyl-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: C([Li])CCC.[I:6]I.Br[C:9]1[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[N:13][CH:14]=1>C(OCC)C.CCCCCC>[Cl:15][C:12]1[C:11]([Cl:16])=[CH:10][C:9]([I:6])=[CH:14][N:13]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Clc1cc(I)cnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In one embodiment of the present invention, 5-bromo-2,3-dichloropyridine is dissolved in ethyl ether and cooled to about -78° C. A slight excess molar quantity of n-butyl lithium, dissolved in hexane, is slowly added to the reaction mixture with mild agitation. After about 0.5 hour of stirring, a slight excess molar quantity of I2, dissolved in ethyl ether, is added to reaction mixture with mild agitation. After about 0.5 hour of stirring, the reaction mixture is allowed to warm to room temperature and the 2,3-dichloro-5-iodopyridine is isolated employing standard separatory and purification techniques.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][C:6](=[N:22]OC(NCCC)=O)[C:5]1=[O:30]>CO.[C].[Pd]>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][CH:6]([NH2:22])[C:5]1=[O:30]
Reactant: CCCNC(=O)ON=C1CN(c2ccccc2F)c2ccccc2N(COC)C1=O
Agent: [Pd]
Solvent: CO
Product: COCN1C(=O)C(N)CN(c2ccccc2F)c2ccccc21
Reaction time: 4 h
Yield: 25 %

Procedure:
1-Methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.52 g) was dissolved in methanol (30 ml), 10% palladium carbon (0.60 g) was added thereto, the mixture was swung for 4 hours under hydrogen atmosphere (3.5-3.0 kg/cm2). Palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1), to thereby obtain 0.48 g of the titled compound as yellow-brown amorphous.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-methoxyphenyl)-1-propanone and 0.2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][CH:26]([NH2:28])[CH3:27]>>[OH:24][CH2:25][CH:26]([NH:28][C:20]([C:17]1[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:27]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC(C)CO)[nH]n1
Yield: 32 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (13 mg, 32%) which was obtained as an off white solid. MS: m/e=374.4 [M+H]+.
Reaction SMILES: I[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C(COC)OC.O.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:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccncc1I
Reactant: Cc1ccccc1B(O)O
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: O
Solvent: COCCOC
Product: Cc1ccccc1-c1cnccc1C(=O)O
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a suspension of 1.05 g (4.21 mmol) 3-iodo-isonicotinic acid in 15 ml dimethoxyethane were added successively 0.243 g tetrakis(triphenylphosphine)palladium(0), 4.2 ml 2 M sodium carbonate solution in water and 0.69 g (5.05 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 18 h. After cooling to room temperature the phases were separated and the organic phase was washed twice with water (pH=9). The combined aqueous layers were than adjusted to pH=3 and extracted with five portions ethyl acetate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.68 g (75%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH2:36][C:37]([N:39]([CH3:40])[CH3:41])=[O:38])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)CC[C@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CCC(=O)N(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.58 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 70-2 (5.64 mmol, crude form) as starting materials, respectively 0.64 g (Isomer A, colorless powder) and 1.14 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH:5]=[N:4][C:3]=1[CH3:17].[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH3:27])=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH3:27])=[CH:21][C:20]=1[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH:5]=[N:4][C:3]=1[CH3:17]
Reactant: Cc1ncc(-n2nnc3ccccc32)nc1Cl
Reactant: COc1cc(Cl)c(B(O)O)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(-c2nc(-n3nnc4ccccc43)cnc2C)cc1C
Temperature: 110 °C
Yield: 50 %

Procedure:
To a stirred solution of 83 mg 1-(6-Chloro-5-methyl-pyrazin-2-yl)-1H-benzotriazole (0.29 mmol) and 58 mg 2-chloro-4-methoxy-5-methyl-phenyl boronic acid (0.29 mmol) in 0.3 mL toluene was added 0.29 mL 2 M Na2CO3 (aq). After 10 min 10 mg (pbbp)Pd(Cl)2 was added as a solid and the resulting suspension was heated at 110° C. for 16 h. The organic phase was directly subjected to column chromatography eluting with hexane ethyl acetate (0.1% Et3N) to provide the title compound in 50% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.Cl.[NH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:42])[C@@H:30]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+:38]([O-:40])=[O:39])[NH2:31])=[CH:23][CH:22]=1)=[O:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH:28][C:29](=[O:42])[C@@H:30]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+:38]([O-:40])=[O:39])[NH:31][C:12](=[O:14])[CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:25][CH:26]=1)=[O:18]
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: Cn1cc(CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccccc21
Yield: 34 %

Procedure:
Prepared analogously to Example 69a) from 1-methyl-1H-indole-3-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 34% of theory. Colourless, amorphous substance, which was used in the following step without purification.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(C)C)(=O)C.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH2:35][CH2:36][C:37](=O)[C:38]#[C:39][Si](C)(C)C)[C:31]([O:33]C)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].FC(F)(F)C(O)=O>>[C:22]([O:26][C:27]([N:29]1[C@@H:37]([C:38]#[C:39][CH3:1])[CH2:36][CH2:35][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@H](CCC(=O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CC#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Temperature: -10 °C

Procedure:
A 2-L, 3-neck jacketed round-bottomed flask equipped with an overhead mechanical stirrer, N2-inlet, temperature probe and addition funnel was charged with sodium triacetoxyborohydride (93.0 g, 0.44 mol), isopropyl acetate (100 g) and an isopropyl acetate solution obtained from Example 1 (27.8 wt %, 410 g, 0.33 mol). The resulting mixture was chilled to −10° C. (internal temperature). Trifluoroacetic acid (170 g, 1.5 mol) was added dropwise by addition funnel over a 2-hour period. The internal temperature was adjusted to 10° C. and the mixture was stirred until HPLC analysis indicated complete consumption of starting material (about 15 hours). The reaction was poured into 750 g of 25% K2HPO4 (prepared by dissolving 250 g of K2HPO4 in 750 g of water). The pH of the mixture was adjusted to 6.6 using 20% KOH (prepared by dissolving 100 g of KOH in 400 g of water). The layers were separated. The organic layer was washed with 25% K2HPO4 (250 g) and with water (250 g). The organic layer was distilled to remove isopropyl acetate, which was chased with ethanol to a final volume of about 250 mL. The solution was cooled to 0° C. and 3.5 M LiOH solution (prepared by dissolving 37 g of LiOH—H2O in 250 g of water) was added such that the temperature remained below 20° C. The reaction progress was followed by HPLC until no ester remained (typically about 2 hours). The ethanol was removed by distillation under vacuum and the resulting aqueous layer was extracted with methyl tert-butyl ether (190 g). The methyl tert-butyl ether layer was extracted with water (100 g) and discarded. The combined aqueous layers was cooled to 0° C. and neutralized to pH 7 with concentrated HCl. Isopropyl acetate (220 g) was added and the pH was adjusted to 3 with concentrated HCl. The layers were separated and the aqueous layer was extracted with isopropyl acetate (220 g). The combined organic layers were washed with water (100 g). The organic solution was distilled under vacuum to a total volume of about 180 mL, and cooled to 0° C. Crystals formed over a 30-minute period. Heptanes (50 g) was added dropwise over a 2-hour period and the resulting mixture was stirred for 2 hours at 0° C. The mixture was filtered and the solid was washed with cold 1:1 isopropyl acetate/heptanes (50 mL) and dried under vacuum to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.24 (s, 9H) 1.45 (s, 9H) 1.87-2.04 (m, 1H) 2.11-2.28 (m, 1H) 2.57-2.81 (m, 2H) 3.75 (s, 3H) 4.23-4.40 (m, 1H) 4.99-5.14 (m, 1H).
Reaction SMILES: [NH:1]([CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)N.C(OCC)(=O)C.[H][H]>[Pt](=O)=O.C(O)(=O)C>[NH2:1][CH2:3][C:4]1([OH:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: NNCC1(O)c2ccccc2C=Cc2ccccc21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NCC1(O)c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 6 g. of 5-hydrazinomethyl-5H-dibenzo[a,d] cyclohepten-5-ol, 160 mg. of platinum dioxide, 60 ml. of ethyl acetate and 60 ml. glacial acetic acid is hydrogenated at room temperature and about atmospheric pressure for 9 hours during which the uptake of hydrogen is about stoichimetric. The resulting mixture is filtered, evaporated in vacuo and the residue treated with 10% sodium bicarbonate solution and then with methylene chloride. The separated aqueous phase is extracted with methylene chloride and the combined organic phases extracted with water and then with saturated sodium chloride solution, followed by drying and evaporation in vacuo. The residue is crystallized from diethyl ether to obtain 5-aminomethyl-5H-dibenzo[a,d] cyclohepten-5-ol, m.p. 117°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[CH2:22][C:21](=[O:23])[CH2:20][CH2:19][O:18]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:21]2([OH:23])[CH2:20][CH2:19][O:18][C:17]([CH3:24])([CH3:16])[CH2:22]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CC1(C)CC(=O)CCO1
Product: CC1(C)CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Yield: 72 %

Procedure:
Using the procedure described in the 2nd paragraph of the portion of Example 3 which is concerned with the preparation of starting materials, 3-benzyloxybromobenzene (1.34 g) was reacted with 2,2-dimethyltetrahydropyran-4-one (0.65 g) to give 4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran (1.14 g, 72%), as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH2:14])=[NH:13])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C>[NH2:13][C:12]1[NH:14][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: N=C(N)NS(=O)(=O)c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC1=NS(=O)(=O)c2cnccc2N1

Procedure:
A mixture 0.25 g of 4-chloro-3-pyridylsulfonylguanidine (Preparation 14) and 0.25 g of potassium carbonate in 5 cm3 of dioxane/DMF (80/20) is heated at reflux for 24 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCNCCC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A solution of 1.01 g (0.005 mole) of 3-butylamino-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) gave 1.6 g of 3-[butyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propionic acid tert-butyl ester (IV-44)
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (17 g, 55 mmol) and a stir bar were added to a 500 mL round bottom flask. The flask was sealed and flushed with nitrogen and anhydrous diethyl ether (200 mL) added via cannula. A solution of phytanyl mesylate (23) (10.9 g, 28.9 mmol (FW=377)) in anhydrous ether (50 mL) was also added via canulla, and the suspension stirred overnight. The following morning a precipitate had formed on the side of the flask. Chilled water (200 mL) was added (ppte dissolved) and the mixture transferred to a 1000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×150 mL) and all ether phases combined. The ether phase was washed with water (2×150 mL), brine (150 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated, and purified by flash chromatography. Final yield 9.5 g (26.3 mmol, 91.1%).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10].[CH3:15]O>>[F:5][C:6]([F:14])([F:13])[CH2:7][CH:8]([OH:12])[C:9]([O:11][CH3:15])=[O:10]
Reactant: CO
Reactant: O=C(O)C(O)CC(F)(F)F
Solvent: O=S(Cl)Cl
Product: COC(=O)C(O)CC(F)(F)F
Temperature: 70 °C

Procedure:
Thionyl chloride (0.139 ml, 1.90 mmol) was added dropwise to a solution of 12-2 (200 mg, 1.27 mmol) in MeOH (2 ml) at room temperature. After addition was complete, the reaction was heated in a sealed vessel at 70° C. for 2 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with 7N NH3/MeOH (3 mL) and filtered to remove insolubles. The filtrate was concentrated to dryness to afford 12-3 as a clear oil.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[C:20]1([C:7]([C:8]2[NH:28][N:27]=[N:26][N:9]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:15][CH2:14][CH:13]2[CH2:19][CH2:18]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
Thus 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile described in U.S. Pat. No. 3,318,869 is reacted with sodium azide in DMF to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. This tetrazole is reacted with ethyl chloroglyoxylate in pyridine at -6° C to provide ethyl [1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylate hydrochloride. This ester is hydrolysed in aqueous potassium hydroxide to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylic acid. Heating this acid for 15 minutes in an oil bath at 130°-140° provides 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole. The hydrochloride salt melts at 233°-234.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:18]1([SH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(Br)n1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(SC2CCCCC2)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
After 6-bromo-pyridine-2-carboxylic acid methyl ester (0.30 g, 1.39 mmol) was dissolved in DMF (4 mL), K2CO3(0.575 g, 4.16 mmol) and cyclohexanethiol (0.25 mL, 2.08 mmol) were added thereto in turn, and the mixture was stirred at 70° C. for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, extracted with EtOAc, and purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.162 g, 46%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.C([Si](C)(C)[O:44][CH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=[N:52]2)[CH2:47][CH2:46]1)(C)(C)C>>[OH:44][C@H:45]1[CH2:46][CH2:47][C@H:48]([N:51]2[CH:55]=[C:54]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]4[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]5[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=5)[N:10]=4)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=3)[CH:53]=[N:52]2)[CH2:49][CH2:50]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Reactant: CC1(C)OB(c2cnn(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn([C@H]5CC[C@H](O)CC5)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Compound 137A). After Suzuki reaction and SPE pre-purification, dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was sent to MDP for purification. MS (ES+): m/z 702.34 (100) [MH+]; HPLC: tR=0.96 min (UPLC, purity).