Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH:12]=[CH2:13])[C:6]=1[OH:14].S(OC)(O[CH3:23])(=O)=O>[OH-].[K+]>[CH3:23][O:14][C:6]1[C:7]([CH2:11][CH:12]=[CH2:13])=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: C=CCc1cccc(Oc2ccccc2Cl)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: C=CCc1cccc(Oc2ccccc2Cl)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
An aqueous solution (100 ml) of potassium hydroxide (17.0 g) was added all at once to a mixture of 2-(2-chlorophenoxy)-6-allylphenol (22.0 g) and dimethyl sulfate (23.0 g) under cooling. The mixture was stirred at room temperature for 30 minutes and extracted with diethyl ether. The extract was washed with water 3 times, dried over magnesium sulfate and then evaporated. The oily residue was subjected to distillation under reduced pressure to give colorless oil of 2-chlorophenyl 2-methoxy-3-allylphenyl ether (22.0 g). bp 149° C./0.8 mmHg.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([NH:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC2CC2)cn1
Yield: 89 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using cyclopropylamine instead of ethanolamine to the title compound (SiO2, heptane:ethyl acetate=70:30 to 0:100, 201 mg, 89%) which was obtained as a white solid. MS: m/e=349.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=O)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[NH4+]>CO.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[N:12][OH:13])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1ccnc(Cl)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccnc(Cl)c1F
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-fluoro-pyridine-4-carbaldehyde (1.20 g, 5.64 mmol) in MeOH (48 mL) and water (8 mL) were added hydroxylamine hydrochloride (0.59 g, 8.46 mmol) and ammonium acetate (1.30 g, 16.9 mmol), and stirring was continued at RT overnight. The reaction mixture was concentrated in vacuo, and the residue was suspended in CH2Cl2/MeOH 9:1. The precipitate was filtered off, washed with CH2Cl2 and dried to afford the title compound as a white solid. MS (LC/MS): 175.0 [M+H]+; tR (HPLC conditions b): 2.78 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](O)c1ccccc1F
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1F

Procedure:
In a similar manner as described for example B31, 2.31 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.92 g of (1S)-1-(2-fluorophenyl)ethanol, 3.67 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.53 g of di-tert-butyl azodicarboxylate in 65 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.O1CCOCC1.[NH3:34]>O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:34])=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Reactant: N
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.2 g. (31.5 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride and 150 ml. dioxan, there is added dropwise, while stirring at ambient temperature, within the course of 30 minutes, a solution of 100 ml. concentrated aqueous ammonia in 50 ml. dioxan. The reaction mixture is stirred for a further 30 minutes and then sufficient water is added thereto to precipitate out the desired amide. After suction filtration, drying and recrystallisation from toluene, there are obtained 8.5 g. (75% of theory) of amide; m.p. 170°-173° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[NH2:8][C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)=[N:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)CC1
Yield: 87.1 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyrimidine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-4-ylcarbamate (683 mg, 3.5 mmol) followed by reduction to afford the desired product (792 mg, 87%) as a purple solid: ESI MS m/z 294 [C14H23N5O2+H]+.
Reaction SMILES: O[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[NH:48]1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][N:48]5[C:49](=[O:56])[C:50]6[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=6)[C:47]5=[O:57])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C/C(=N\OCCO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C(=N\OCCN1C(=O)c2ccccc2C1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.3 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-hydroxyethyl oxime (example 23) (200 mg, 0.55 mmol) in THF (10 mL) were added triphenylphosphine (144 mg, 0.55 mmol), isoindoline-1,3-dione (81 mg, 0.55 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (111 mg, 0.55 mmol) sequentially. The mixture was stirred at rt for 48 h and concentrated in vacuo. The residue was purified by column chromatography to afford 120 mg (42%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.81 (d, 1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.52 (dd, 1H), 6.19 (s, 2H), 4.53 (t, 2H), 3.97 (t, 2H), 2.20 (s, 3H). LCMS (method B): [MH]+=493, tR=2.52 min.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCO1
Product: O=C1CCCN1Cc1ccccc1

Procedure:
6.97 g (0.06 M) of γ-butyrolactone is mixed with 6.97 g (0.065 M) of benzylamine and heated at 190° for 24 hours. Excess benzylamine was removed at reduced pressure and the residue was distilled at 125°-130°/1 mm.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>ClCCCl.CC(O)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:3]3[N:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Fc1ccc(-c2nc3c(Cl)ncnc3o2)cc1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Fc1ccc(-c2nc3c(Nc4ccc(F)c(Cl)c4)ncnc3o2)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine (85 mg, 0.34 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 2 ml) was added 3-chloro-4-fluoroaniline (50 mg, 0.34 mmol). The mixture was heated at 90° C. for 1 day. After cooling down to room temperature, the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (0.1 g, 82%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)[CH2:21][C:20]2=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([C:31]3[N:32]=[C:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[S:34][CH:35]=3)[CH2:21][C:20]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(c1csc(N)n1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)CC(c1csc(NC(=O)c2ccc4c(c2)NC(=O)CS4)n1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid and 4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-thiazol-2-ylamine as starting materials.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[C:1]([C:3]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C#N)cc1F
Temperature: 45 °C
Yield: 43 %

Procedure:
To a flask containing methyl 4-cyano-2-fluorobenzoate (1.61 g, 9.0 mmol) was added fuming nitric acid (15 mL) followed by concentrated sulfuric acid (4 mL). The mixture was heated to 45° C. for 15 h before cooling to room temperature. The solution was then poured into ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide methyl 4-cyano-2-fluoro-5-nitrobenzoate (859 mg, 3.83 mmol, 43% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 8.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.3) and (S)-pyrrolidin-3-ol to afford an off-white crystalline powder. HPLC (Condition 4) tR=5.83 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=446.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1([CH2:26][OH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:26]([O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OCc1ccccc1
Product: COc1ccc2c(OCc3ccccc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenyl-methanol to give (1-benzyloxy-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CO.[C].[Rh].[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)c(F)c3)C2=N1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)c(F)c3)C2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
To a solution of 9-(2-fluorobiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in THF/methanol (30 mL/30 mL) was added 5% rhodium carbon (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 day. Platinum (IV) oxide (40 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 9 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, the obtained residue was purified by recrystallization (THF-ethyl acetate/diisopropyl ether) to give the title compound (121.2 mg).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[C:12]2=[O:31])[CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:13]2[C:14]([CH3:17])([CH3:16])[CH2:15][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:32])=[O:2])[C:12]2=[O:31])=[CH:20][C:21]=1[C:27]([F:30])([F:29])[F:28])#[N:26]
Reactant: COC(=O)c1cccc(CN2CC(C)(C)C(Oc3ccc(C#N)c(C(F)(F)F)c3)C2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CN(Cc2cccc(C(=O)O)c2)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
The compound obtained in Example 25, (±)-3-[3-(4-cyano-3-trifluoromethyl-phenoxy)-4,4-dimethyl-2-oxo-pyrrolidin-1-ylmethyl]-benzoic acid methyl ester, (0.128 g, 0.29 mmol) was dissolved in 4 mL THF and 1.0 mL 1 M NaOH was added. The reaction was stirred at ambient temperature overnight. The reaction mixture was acidified with 1 N HCl to pH ˜3 and extracted into ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated in vacuo. The material was triturated with diethyl ether and filtered to obtain the carboxylic acid as a white solid (0.105 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.CC([O-])=O.[Na+].[NH2:16][OH:17].Cl>CCO>[Cl:1][C:2]1[C:7]([CH:8]=[N:16][OH:17])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,6-dichloro-5-pyrimidinecarbaldehyde (8.00 g, 44.8 mmol), NaOAc (3.7 g, 1.0 eq) and NH2OH.HCl (3.1 g, 1.0 eq) in EtOH (320 mL) was stirred at rt for 2 h. The reaction mixture was filtered, concentrated and purified by column chromatography on silica gel (dry loading, first DCM then DCM/EtOAc, 1/9) to give 4,6-dichloro-5-pyrimidinecarbaldehyde oxime as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:38][C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:40](=[O:41])[C:39]([OH:38])([CH3:44])[CH3:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C(C)(C)O)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100 μl), followed by 2-chloro-1,1-dimethyl-2-oxoethyl acetate (24 mg, 150 μmol). The stirring was continued for 20 min at r.t., then the solvent was removed under reduced pressure, and the residue dissolved in ethanol (1 ml). Aqueous sodium hydroxide solution (1 M, 1 ml) was added, and the mixture was stirrer at 80° C. for 30 min. Then it was cooled to r.t., acidified with TFA, and concentrated under reduced pressure. The product was purified by semi-prep. HPLC. Yield 22 mg (96%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C:25]3[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Temperature: 86 °C
Yield: 91.6 %

Procedure:
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.0 g, 6.59 mmol) was mixed with 4-fluorobenzaldehyde (1.06 mL, 9.89 mmol), cesium carbonate (4.30 g, 13.19 mmol) in DMF (6 mL). The reaction mixture was heated at 86° C. overnight. After cooling to room temperature, the reaction mixture was poured onto ice water. The solid was collected by filtration to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (2.46 g, 92%). 1H NMR (CDCl3) δ 7.19 (m, 5H), 7.46 (m, 2H), 7.78 (d, J=8.64 Hz, 2H), 8.10 (d, J=8.70 Hz, 2H), 8.44 (s, 1H), 8.59 (d, J=8.70 Hz, 2H), 10.03 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[O:13][C@H:14]3[C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21][C@@H:20]4[C@@:15]53[CH2:16][CH2:17][N:18]([CH3:29])[C@@H:19]4[CH2:28][C:10]([C:11]=25)=[CH:9][CH:8]=1)(=O)=O.[CH3:32][N:33](C)C=O>C(OCC)(=O)C.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-]#N.[Zn+2].[C-]#N>[CH3:29][N:18]1[CH2:17][CH2:16][C@@:15]23[C:11]4[C:10]5[CH2:28][C@@H:19]1[C@@H:20]2[CH2:21][CH2:22][C:23]1([C@@H:14]3[O:13][C:12]=4[C:7]([C:32]#[N:33])=[CH:8][CH:9]=5)[O:24][CH2:25][CH2:26][O:27]1
Reactant: CN1CC[C@]23c4c5ccc(OS(=O)(=O)C(F)(F)F)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Temperature: 40 °C
Yield: 63 %

Procedure:
To a solution of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate (20.77 g, 45.0 mmol) in degassed dimethylformamide (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (5.21 g, 4.50 mmol). After heating to 40° C., zinc cyanide (3.18 g, 27.0 mmol) was added and the reaction mixture heated at 110° C. for 6 hours. The reaction mixture was cooled to room to temperature and diluted with ethyl acetate and filtered through a pad of celite. The filtrate was diluted further with ethyl acetate and washed with water (3×500 mL). The aqueous phase was basified with sodium hydrogen carbonate solution and re-extracted with ethyl acetate and the combined organics dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica chromatography (100% dichloromethane to 5% NH3/methanol in dichloromethane) gave (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (10.0 g, 91% pure LCMS, 63% yield over three steps); [M+H]+339.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([CH:18]=O)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:23]([NH:25][CH:26]3[CH2:28][CH2:27]3)=[O:24])[CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:17]=[C:16]([CH2:18][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:23]([NH:25][CH:26]3[CH2:28][CH2:27]3)=[O:24])[CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(CN3CCCC3)c2c1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
3-(2-Benzyl-4-formyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.13 g) was dissolved in dichloromethane (10 mL). Pyrrolidine (0.064 g) was then added and the mixture stirred for 10 minutes before adding sodium triacetoxyborohydride (0.25 g). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue purified (SiO2, eluting with 5% methanol in dichloromethane) to give the title compound as a solid (0.038 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:19])=[N:14]2)[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CCO>[C:10]([C:8]1[CH:7]=[C:6]([N:13]2[C:17](=[O:18])[C:16](=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=3)[C:15]([CH3:19])=[N:14]2)[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1)([OH:12])=[O:11]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC1=NN(c2cc(C(=O)O)cc(C(=O)O)c2)C(=O)C1
Solvent: CCO
Product: CC1=NN(c2cc(C(=O)O)cc(C(=O)O)c2)C(=O)C1=Cc1ccc(N(C)C)cc1

Procedure:
A slurry composed of 1-(3,5-dicarboxyphenyl)-3-methyl-2-pyrazoline-5-one (44.6 grams, 0.17 mol), 4-dimethylaminobenzaldehyde (26.9 grams, 0.18 mol) and EtOH (500 mL) was heated at reflux for three hours. The reaction mixture was chilled in ice and the resulting crude orange product was isolated by filtration and washed with EtOH (200 mL). The product was purified by three repetitive slurries of the solid in acetone (1.4 1) at reflux and filtering to recover the dye. The mp of the product was above 310° C. The NMR and IR spectra were consistent with the structure assigned. The C, H and N elemental analyses were in agreement with those calculated for the empirical formula for the dye.