Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:55])[CH2:24][CH2:25][CH2:26][N:27]([C:29]4[CH:30]=[CH:31][C:32]([C:35]5[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43]CC6C=CC(OC)=CC=6)=[C:37]([O:53][CH3:54])[CH:36]=5)=[N:33][CH:34]=4)[CH3:28])=[CH:19][N:18]=3)=[CH:11][C:10]=2[O:56][CH3:57])=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:55])[CH2:24][CH2:25][CH2:26][N:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[C:39]([O:41][CH3:42])[C:38]([OH:43])=[C:37]([O:53][CH3:54])[CH:36]=4)=[N:33][CH:34]=3)[CH3:28])=[CH:19][N:18]=2)=[CH:11][C:10]=1[O:56][CH3:57]
Reactant: COc1ccc(COc2c(OC)cc(-c3ccc(N(C)CCCN(C)c4ccc(-c5cc(OC)c(OCc6ccc(OC)cc6)c(OC)c5)nc4)cn3)cc2OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc(N(C)CCCN(C)c3ccc(-c4cc(OC)c(O)c(OC)c4)nc3)cn2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of N,N′-bis[2-[4-(4-methoxybenzyloxy)-3,5-dimethoxyphenyl]-5-pyridyl]-N,N′-dimethyl-1,3-propanediamine (72.0 mg, 0.089 mmol) in methylene chloride (1.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. A solution of the residue in chloroform was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield N,N′-bis[2-(4-hydroxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethyl-1,3-propanediamine as a pale yellow oil (43.0 mg, yield: 86%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:25]=[O:26]>C1COCC1.CN1C(=O)N(C)CCC1>[OH:26][CH2:25][C:13]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C=O
Reactant: CCOC(=O)C1c2ccccc2Oc2ccccc21
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)c2ccccc2Oc2ccccc21
Temperature: -50 °C
Yield: 68 %

Procedure:
A mixture of 1.5 g (5.9 mmol) of ethyl 9H-xanthene-9-carboxylate in 20 ml of THF and 1.6 ml of DMPU under an inert atmosphere is cooled to −50° C. 4 ml (6.4 mmol) of BuLi (1.6 M in hexane) are added dropwise to this medium with stirring, and the medium is then left stirring for 10 minutes at −40° C. After allowing the reaction medium to warm to 10° C., a flow of formaldehyde generated from 5.4 g (0.18 mol) of sublimed paraformaldehyde entrained by a stream of nitrogen is bubbled in. After stirring for 2 hours at room temperature, the suspension is dispersed in 50 ml of water. The reaction medium is then extracted twice with 100 ml of ether. The combined organic phases are dried over Na2SO4. After evaporation, the residual oil is chromatographed on silica. Eluent: CH2Cl2. 1.1 g of a yellow oil are obtained (yield: 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:31]=[N:32][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: CCCCOc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[C:12]([C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:25]3[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[CH:10]=1)#[N:13]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 5-bromothiophene-2-sulfonamide (117 mg, 0.5 mmol) according to general procedure II. Obtained as an off-white solid (80 mg, 35%). MS (ISP) 473.1 [(M+H)+]; mp 267–269° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]1([C:20]2[CH:28]=[C:27]3[C:23]([CH2:24][C:25](=[O:29])[NH:26]3)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1CCCCC1.C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:24]1[C:23]2[C:27](=[CH:28][C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:21][CH:22]=2)[NH:26][C:25]1=[O:29]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(-c3ccccc3)ccc21
Yield: 78.5 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 105 mg 6-phenyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 146 mg (78%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][C:14]=1[CH3:31])[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:15][C:14]=1[CH3:31])[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Oc1cc2c(cc1Cl)C(C(=O)O)CCO2
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate (0.022 g, 0.042 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.087 ml, 0.087 mmol). The reaction was stirred overnight and then concentrated. The residue was taken up in water and acidified with 1M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by preparatory thin layer chromatography eluting with 95:5:1 dichloromethane/methanol/glacial acetic acid to yield 11 mg of the title compound (53% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@@H:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6][C:5]=1[OH:30].C([O-])([O-])=O.[K+].[K+].[C:38]([O:41][CH2:42]Br)(=[O:40])[CH3:39]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@@H:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6][C:5]=1[O:30][CH2:39][C:38]([O:41][CH3:42])=[O:40]
Reactant: CC(=O)OCBr
Reactant: COC(=O)c1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1C(=O)OC

Procedure:
5-((2S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-2-hydroxy-benzoic acid methyl ester of Step C (213 mg, 0.49 mmol) is stirred in acetone (2 mL) with powdered K2CO3 (207 mg, 1.5 mmol) and bromomethyl acetate (95uL, 1.5 mmol) at RT under N2 and then at 50° C. The reaction is diluted with EtOAc (100 mL) and washed with 1N HCl (30 mL) and saturated NaHCO3 (2×30 mL). The organics are dried (MgSO4), filtered, concentrated and purified by flash column chromatography to provide 5-((2S)-2-benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:36])[CH2:34][CH3:35]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:4]([CH2:3][CH2:2][N:30]3[CH:31]=[C:27]([CH3:26])[N:28]=[CH:29]3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3cnc(C)c3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=428.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 4-methyl-1H-imidazole.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2cnc(Cl)nn2)c1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2cccc(F)c2)nn1
Temperature: 65 °C
Yield: 90.2 %

Procedure:
A solution of 3-chloro-6-(3-fluoro-phenyl)-[1,2,4]triazine (2.09 g, 10.0 mmol) in 13.6 ml of dry pyridine was cooled to 0° C. with ice bath and 1.7 ml of hydrazine hydrate was added. The mixture was then heated to 65° C. and maintained this temperature for ca. 0.5 hour. After cooling down to room temperature, the mixture was poured into ice-water. The resulting solid was recovered by filtration and washed well with water, dried and scratched with hexane to give title compound (1.85 g, 90.2%) as a yellow crystalline solid: 1H NMR (DMSO-d6): δ 8.97 (b, 1H), 8.90 (s, 1H), 7.89-7.82 (m, 2H), 7.59-7.51 (m, 1H), 7.30-˜7.24 (m, 1H), 5.47 (b, 2H); MS (m/z) 206 [M+H+]+.
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([NH:22]C(=O)OC(C)(C)C)=[N:20][CH:21]=3)[N:13]=[C:12]3[C:8]=2[N:9]=[C:10]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[N:11]3[CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[N:1]1([C:7]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)[N:13]=[C:12]3[C:8]=2[N:9]=[C:10]([N:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[N:11]3[CH2:30][C:31]([F:32])([F:34])[F:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
tert-Butyl {5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-yl}carbamate (1.18 g, 2.09 mmol) was dissolved in methylene chloride (10 ml) followed by the addition of trifluoroacetic acid (10 ml) with ice cooling and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure followed by the addition of toluene and evaporated again under reduced pressure to give the title compound (1.5 g, 100%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1C=CC=CC=1>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:15]([NH:14][CH2:12][CH3:13])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C)co1
Reactant: CCN=C=O
Solvent: c1ccccc1
Product: CCCCN(C(=O)NCC)c1nc(C)co1

Procedure:
A solution of 2-butylamino-4-methyloxazole (15.0 g, 0.0972 mol) and ethyl isocyanate (7.6 g, 0.107 mol) in dry benzene was heated under reflux for 2 hours and then evaporated to dryness. The residual oil was dissolved in ether and the solution was washed with 2 N HCl, dried and evaporated. The residue was distilled under vacuum b.p. 128° C./1.0 mm. IR 3275, 1696, 1590 cm-1.
Reaction SMILES: [C:1]([O:12]C)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16].Cl>CO>[C:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][NH2:16])=[O:7])=[CH:4][CH:3]=1)([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)O)cc1

Procedure:
In 1 l of methanol was dissolved 180 g of monomethyl terephthalate, and the solution was slowly added dropwise to 500 ml of hydrazine hydrate (50%) at room temperature while stirring. After the drop-wise addition, the mixture was heat-refluxed for 5 hours while stirring. A hydrochloric acid aqueous solution was slowly added to the reaction mixture to adjust to a pH of about 1 to thereby precipitate white crystals. Two liters of water was added to the system, followed by stirring for a while. The formed crystals were collected by filtration under reduced pressure, washed twice with 200 ml of water, and dried to obtain 160 g of p-carboxybenzhydrazide (melting point: 235-236° C.).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][S:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=O)=[CH:18][CH:17]=1.C(OCC)(=O)C>O1CCCC1>[CH3:14][S:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[CH:3][C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: CSc1ccc2c(c1)C(=O)CCC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc2c(c1)C(=CC#N)CCC2
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere and at 0° C., diethyl cyanomethylphosphonate (7.6 ml, 46.8 mmol) is added dropwise to a suspension of sodium hydride (2.25 g, 46.8 mmol) in 50 ml of tetrahydrofuran. Stirring is carried out at 0° C. for 30 minutes; the compound obtained in Step C (6 g, 31.2 mmol), dissolved in 50 ml of tetrahydrofuran, is then added and the reaction mixture is stirred at ambient temperature for 3 hours. After hydrolysis and extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel (eluant: petroleum ether/dichloromethane 50/50) to yield the unsaturated nitrile of the title.
Reaction SMILES: [C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:41])[NH:9][C:10]3([CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][N:27]=[C:28]5[NH:31]CC5C=CC(OC)=CC=5)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:31][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([C:19]([N:16]3[CH2:17][CH2:18][C:10]4([NH:9][C:8](=[O:41])[C:7]5=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]=[C:12]5[CH2:11]4)[CH2:14][CH2:15]3)=[O:20])[CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)N4CCC5(CC4)Cc4cn(C(C)(C)C)nc4C(=O)N5)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccnc(N)c4c3)CC1)C2
Temperature: 65 °C
Reaction time: 19 h
Yield: 32.2 %

Procedure:
To a solution of 2′-tert-butyl-1-(1-(4-methoxybenzylamino)isoquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (28 mg, 0.051 mmol) in trifluoroacetic acid (0.51 mL) was added anisol (8.3 μL, 0.076 mmol). The reaction was heated to 65° C. and stirred for 19 hours. The reaction was concentrated. Purification by reversed-phase HPLC gave the title compound (7.1 mg, 32%). +ESI (M+H) 433.2; HPLC retention time 1.79 minutes (Method A).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:24]CC)[CH:6]([PH:10]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)=[O:11])C(C)C)C.[OH-].[Na+].CO.[CH2:33]1[CH2:37]OC[CH2:34]1>>[OH:24][C:5]([CH2:6][PH:10]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)=[O:11])([CH2:27][CH:33]([CH3:37])[CH3:34])[C:4]([OH:3])=[O:28]
Reactant: CCOC(=O)C(C)(OCC)C(C(C)C)[PH](=O)CSc1ccc2ccccc2n1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(O)(C[PH](=O)CSc1ccc2ccccc2n1)C(=O)O

Procedure:
2-(Ethoxy)(quinolin-2-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (4.5 g) was dissolved in 100 mL THF and 12.5 mL of 2N NaOH was added together with enough methanol to make the solution homogeneous. After 18 hours the THF was removed by evaporation, the residue diluted with 50 mL H2O and washed with 50 mL ethyl acetate. The aqueous phase was then acidified to pH 4, and the product extracted with 50 mL ethyl acetate (2×). The ethyl acetate was washed with 20 mL brine, dried with MgSO4 and evaporated to yield 3.8 g of 2-(hydroxy)(quinolin-2-ylthiomethyl)phosphinoylmethyl-4-methylpentanoic acid as a yellow oil, MS: 368 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)(=O)C.O>[CH:15]1([NH:21][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CNC1CCCCC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
2-Chloro-N-(4-nitrophenyl)-acetamide (11.5g) and cyclohexylamine (10.7g) were heated together 2 hours at 150° and then added to ethyl acetate/water. The product was extracted with ethyl acetate to yield 9.0g, m.p. 123°-125°C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C(OCC)(=O)C>[Cl:11][CH2:12][C:13]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitroaniline (10.0g) and chloroacetyl chloride (15 ml) were refluxed together 1 hour, mixed with ethyl acetate and washed with water 3 times to yield 11.5 g; mp 183°-185°C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]1=[O:20].[I:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[I:21][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:20])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:5]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of 3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 20) (800.0 mg) in acetic acid (13.0 ml) was added in water bath N-iodosuccinimide (784.5 mg) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was added water (20 ml) and the resulting mixture was stirred for thirty minutes, and thereto was added sodium thiosulfate solution (20 ml) and the resulting mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with water to afford 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (819.3 mg).
Reaction SMILES: B#B.[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6].O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:3][CH:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH2:5][OH:6]
Reactant: CC(Cc1ccc(Br)cc1)C(=O)O
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 102 %

Procedure:
Diborane (192 ml of a 1.0 M solution in THF) was added dropwise over 25 minutes to a solution of 2-methyl-3-(4-bromophenyl)propanoic acid (38.9 g) in THF (240 ml) at 0° C. The reaction mixture was stirred for 45 minutes at 0° C. and then allowed to warm to ambient temperature over 2 hours. Water (120 ml) was added followed by solid potassium carbonate (144 g) and then more water (80 ml). The reaction mixture was extracted with diethyl ether (3×250 ml), the combined organic layers were dried (MgSO4) and the solvent was evaporated to give 2-methyl-3-(4-bromophenyl)propanol as a yellow oil (37.4 g), mass spectrum (+ve CI): 248 (M+NH4)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6]1)[NH2:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:1][N:2]=[C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6]1)[NH2:4])(=[O:20])[CH3:19]
Reactant: COc1cc2c(cc1OC)CC(C(N)=NO)C2
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)CC(C(N)=NOC(C)=O)C2
Temperature: 0 °C

Procedure:
A suspension of 6.6 g (28 mmol) 2,3-dihydro-N'-hydroxy-5,6-dimethoxy-1H-indene-2-carboximidamide was stirred in 50 ml of acetic acid anhydride for 1 hour at room temperature. The suspension was subsequently poured out into 500 ml of ice water and, after 2 hours stirring, was drawn off and washed to neutral with water.