Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][CH:15]3[OH:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[CH2:7][C:6]([OH:21])=[CH:5][CH2:4][C:3]2=1.[CH3:22]C(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].O.[OH-].[Na+]>C1C=CC=CC=1.CC(=O)CC>[CH3:22][O:21][C:6]1[CH2:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@:2]([CH3:1])([C:3]=2[CH2:4][CH:5]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]1=[O:20]
Reactant: CC(C)[O-]
Reactant: C[C@]12CC[C@]3(C)C(O)CC[C@H]3[C@@H]1CCC1=C2CC=C(O)C1
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCC(C)=O
Solvent: O
Product: COC1=CCC2=C(CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@]23C)C1

Procedure:
A mixture of 5.0 g of 9alpha-methylestra-2,5(10)-dien-3,17-diol 3 methyl ether and 4.5 g of aluminum isopropoxide in 45 ml of benzene and 45 ml of 2-butanone is stirred and refluxed for 22 hrs., using a water separator. After cooling, the reaction mixture is added to 100 ml. of 2N sodium hydroxide solution and a further 50 ml. of benzene are added. The organic layer is separated, washed with water and saturated sodium chloride and dried over anhydrous sodium sulphate. Removal of the solvent gives a residue which is crystallized from ether/hexane, 1/1 yielding 3-methoxy-9alpha-methyl-estra-2,5(10)-dien-17-one, m.p. 155°-158°, which may be used in Step H, below. Recrystallization from ether yields a product of m.p. 175°-177°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24]1)=[O:22].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](=[O:30])[N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[N:14]=[CH:15][CH:16]=[CH:17][N:18]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)[CH2:24]1)=[O:22]
Reactant: COC(=O)C1CCN(CC(=O)O)C1
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 24 h
Yield: 83.1 %

Procedure:
2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10 from Step 7, 14.7 mmol) and 1-Carboxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 5 from Step 3, 17.6 mmol) were dissolved in 72 ml of DMF. Triethylamine (8 ml, 57 mmol), 1-hydroxybenztriazole (2.29 gm) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.43 gm, 18 mmol) were added and the reaction mixture stirred for 24 hrs. After washing with brine, extracting with dichloromethane, and drying over magnesium sulfate, the mixture was evaporated and chromatographed on silica gel to obtain 5.0 gm of title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[CH:33][N:32]([CH:40]([CH3:42])[CH3:41])[C:31]2=[O:43])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:37]([C:34]2[C:35](=[O:36])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[C:31](=[O:43])[N:32]([CH:40]([CH3:42])[CH3:41])[CH:33]=2)=[O:38])=[CH:20][CH:21]=1
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Nc3ccc(N)cc3)c2cc1OC
Product: COc1cc2nccc(Nc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3)c2cc1OC

Procedure:
This compound was synthesized using N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid the method for example 134. mp=190-193° C.; LCMS m/z=570 (M+1); 1H NMR (DMSO-d6) δ: 10.85 (s, 1H), 8.65 (brs, 2H), 8.26 (d, 1H, J=5.3 Hz), 7.71 (d, 2H, J=8.8 Hz), 7.65 (s, 1H), 7.27-7.47 (m, 7H), 7.23 (s, 1H), 6.75 (d, 1H, J=5.3 Hz), 4.72-4.84 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 1.42 (d, 7H, J=6.8 Hz).
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[S:7][C:8]=1[CH:9]=[O:10])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O>[CH:1]([C:4]1[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[S:7][C:8]=1[C:9]([OH:16])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1c(C=O)sc2ccccc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1c(C(=O)O)sc2ccccc12
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of compound 563-E (1.95 g, 9.5 mmol) in acetone (30 mL) was refluxed for 30 min. A mixture of potassium permanganate (3.02 g, 19.1 mmol) in water (10 mL) was added in portions, and the resultant mixture was refluxed for an additional 30 min. The mixture was cooled to ambient temperature and concentrated in vacuo. A solution of aqueous Na2SO3 (1M, 50 mL) was added followed by sulfuric acid (1 M, 50 mL). Two additional portions of Na2SO3 (1M, 20 mL) were added followed by sulfuric acid (1 M, 20 mL), which resulted in the disappearance of the dark brown color. The resultant suspension was diluted with H2O, filtered, washed with H2O and dried under vacuo to afford 1.52 g of compound 563-F as a yellow solid. MS: m/z 221.1 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][OH:27]
Reactant: NC(CO)CO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC(CO)CO)cc2c1=O
Temperature: 150 °C
Yield: 28.6 %

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 142 mg (1.55 mmol) of 2-amino-1,3-propanediol in a closed vial is heated in a microwave reactor at 150° C. for 20 minutes. After cooling, the reaction mixture is concentrated to dryness and the product purified by HPLC-chromatography on a RP-C18 column using a gradient of water/acetonitril/0.1% TFA as eluent. 35 mg of the title compound are obtained as a red powder, m.p. 126-145° C. (decomp.).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:20][CH2:21][CH3:22])(=[O:19])[C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1>>[CH2:1]([O:16][C:15]1[CH:17]=[CH:18][C:10]([C:9]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:12]=1[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Yield: 97 %

Procedure:
Benzyl bromide was reacted with ethyl vanillate using the conditions described in Example 1 to give ethyl 4-benzyloxy-3-methoxybenzoate in 97% yield m.p. 72°-74° C. Following the procedures described in the portion of Example 6 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium and the resultant product was reacted with ethylmagnesium iodide to give the required starting material as an oil in 20% yield.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(OCCCOc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
1,3-Diphenoxypropane (22.8 g), benzoyl chloride (31 g) and anhydrous aluminum chloride (33 g) are reacted in 1,2-dichloroethane (300 ml) for eighteen hours at 70° to yield 33.4 g (77% of theory) of colorless crystals mp 146°-148°.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:13]([CH2:14][N:15]=[N+]=[N-])=[C:12]([CH3:18])[N:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:13]([CH2:14][NH2:15])=[C:12]([CH3:18])[N:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncn(CC(=O)OC(C)(C)C)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncn(CC(=O)OC(C)(C)C)c1CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-t-butoxycarbonylmethyl-4-methyl-5-azidomethylimidazole (2.9 g) in ethyl acetate (100 ml) containing 10% palladium on carbon (1.5 g) was stirred at room temperature under an atmosphere of hydrogen for 3 h. After removal of the catalyst by filtration through Celite, the filtrate was concentrated to give the amine as a colorless oil: 1H NMR (CD3OD) d 1.48 (s, 9 H), 2.19 (s, 3 H), 3.69 (s, 2 H), 4.81 (s, 2 H), 7.49 (s, 1 H).
Reaction SMILES: C([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])C1C=CC=CC=1.C(O)C>[Pd].O1CCCC1>[OH:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A mixture of 9-benzyloxy-6-phthalimidopurine (11.0 g, 29.5 mmol), 10% palladium on charcoal (2.2 g), ethanol (300 ml) and tetrahydrofuran (500 ml) was stirred at 25° C. for 1 hour under an atmosphere of hydrogen. The suspension was then filtered and the catalyst washed with ethanol. The filtrate was evaporated under reduced pressure and the resulting solid triturated with ether. The solid was collected and then dried to afford the title compound (6.93 g; 83%). IR: υmax (KBr). 2607, 1794, 1735, 1603, 1582, 1467, 1401 cm-1 ; 1H NMRδH [(CD3)2SO] 8.15(4H, s, Ar), 8.95(1H, s, H-2), 9.15(1H, s, H-8), 12.80(1H, br.s, D2O exchangeable, OH). Found: C, 55.34; H, 2.58; N, 24.56%. C13H7N5O3 requires: C, 55.51; H, 2.51; N, 24.91%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH2:31][NH:33][C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: Nc1cccnc1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccc(CNc6cccnc6)o5)cc34)cc2)cc1

Procedure:
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde and 3-aminopyridine were reacted in an analogous manner to Example 10 to give the title compound; δH [2H6]-DMSO 9.82 (1H, b), 8.70 (1H, s), 8.42 (1H, s), 8.11-8.01 (2H, m), 7.80-7.70 (2H, m), 7.62 (2H, d), 7.49-7.25 (5H, m), 7.10-6.95 (5H, m), 6.48 (1H, d), 6.40 (1H, t), 5.10 (2H, s), 4.38 (2H, d); m/z 500 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)([CH2:15][NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:30])[N:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)([CH2:15][NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(=O)NCC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)NCC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
tert-Butyl{1-(3,4-dichlorophenyl)-3,4-dihydroxy-1-[(methylpropionylamino)-methyl]-butyl}-methyl-carbamate (1.09 g) was dissolved in a mixture solvent of tetrahydrofuran (8 mL) and water (8 mL). Sodium periodate (1.0 g) was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (1.05 g, quantative amount). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC=O
Reactant: COC(=O)[C@@H](C)N
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCN[C@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
D-alanine methyl ester (1.5 g, 10.75 mmol) is taken up in 50 mL methanol and is cooled to 0° C. To this is added hexanal (1.3 mL, 10.75 mmol) followed by sodium acetate (2.62 g, 32 mmol). After stirring for 15 minutes at 0° C. sodium cyanoborohydride (440 mg, 7 mmol) is added and the mixture is stirred for further 16 hours at room temperature. The methanol is evaporated and the resulting residue is taken up in ether and is transferred to a separatory funnel, washed with water (2×), dried over sodium sulfate, and is evaporated to give 1.81 g of N-hexyl-D-alanine methyl ester as a colorless oil.
Reaction SMILES: C(C1C=CC(C(N[C:12]2[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=O)=C(OC2CCNCC2)C=1)(C)(C)C.N=C=N.C(Cl)(Cl)Cl>C(O)(C)(C)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:12]=2)=[N:18][CH:19]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Agent: N=C=N
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyrdin-2-yl)benzamide (30 mg, 59 pmnol) in a 4 mL screw cap vial is added polymer-supported carbodiimide (P-EPC, 280 mg @0.85 mmol/g, 4 eq) and a carboxylic acid of choice (120 micromoles, 2 eq), followed by 3 mL of 4:1 (amylene stabilized) chloroform:tert-butyl alcohol. Where acid hydrochloride salts are used, piperidinomethyl polystyrene resin (100 mg @2.6-2.8 mmol/g) is added to effect reaction. The vial is capped, shaken overnight at room temperature, then the mixture is filtered. Retentates are washed with amylene stabilized chloroform (3 mL), and the combined filtrate and wash are concentrated in vacuo to afford the amide derivative of the compound of Example 202.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[ClH:23].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(Cc2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of tert-butyl (3-((4-methylpiperazin-1-yl)methyl)phenyl)carbamate (544 mg, 1.781 mmol) in dioxane (10 mL) was treated with HCl (g) for 10 min, then stirred at RT for 3 h. The mixture was concentrated to dryness to afford crude 3-((4-methylpiperazin-1-yl)methyl)aniline trihydrochloride (505 mg, 90% yield) which was used without further purification. MS (ESI) m/z: 306.2 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19]C)[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[BrH:21]>>[BrH:21].[OH:19][C:12]1[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: Br
Product: CS(=O)(=O)c1cc2c(cc1O)CCNCC2

Procedure:
3-Acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1 g, 0.003 m) in 48% hydrobromic acid (15 ml) was heated to reflux for 16 hours and concentrated in vacuo. The residue was triturated with acetone and recrystallized from methanol-water to give 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrobromide, m.p. 300° (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:12][N:11]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>CC(O)CC.C(Cl)Cl>[CH3:26][N:23]1[CH2:22][CH2:21][N:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:11][N:12]=2)[CH2:25][CH2:24]1
Reactant: CN1CCN(c2nnc(Cl)c3ccccc23)CC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2nnc(Nc3ccc(O)cc3)c3ccccc23)CC1

Procedure:
A mixture of 4-aminophenol (42 mg, 0.38 mmol), 1-chloro-4-(4-methylpiperazin-1-yl)phthalazine (100 mg, 0.381 mmol), and TFA (29 μA 0.38 mmol) was heated in 2-butanol (3 mL) in a sealed tube at 90° C. overnight. Next day LC/MS shows completion of reaction. The reaction was cooled and diluted with DCM. Aqueous sodium bicarbonate was added and the organic layer was collected. The aqueous layer was neutralized with 1N HCl and the product was extracted with DCM. The organic layers were combined, dried over sodium sulfate, and concentrated to afford 4-(4-(4-methylpiperazin-1-yl)phthalazin-1-ylamino)phenol as solid brown material. MS [M+H]=336.2. Calc'd for C19H21N5O: 335.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22].F[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[CH3:22][C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[C:25]1[CH:24]=[CH:29][CH:28]=[C:27]([O:30][CH3:31])[CH:26]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cccc(OC)c3)c(C)c2)c1
Yield: 92.9 %

Procedure:
Compound 1.3 (0.070 g, 0.193 mmol) was coupled with 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (0.0982 g, 0.578 mmol) according to the method reported for preparation of 1.4 to afford 2.1 (0.070 g, 89%) as a colorless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:27])[NH:13][C@@H:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:15]([OH:19])[CH2:16][C:17]#[N:18])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:27])[NH:13][C@@H:14]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:15]([OH:19])[CH2:16][CH2:17][NH2:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCN
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a suspension of LAH (0.6 g) in THF (40 ml) is added at 0° C. a solution of ((1S,2R)-1-Benzyl-3-cyano-2-hydroxy-propyl)-carbamic acid tert-butyl ester (1.1 g) in THF (15 ml). The mixture is stirred for 1 h at 0° C. and then quenched with water and 3N aqueous sodium hydroxide. After filtration the solution is concentrated under reduced pressure and purified by preparative HPLC (gradient of water, 0.1% TFA/acetonitrile, 0.1% TFA from 80/20 to 0/100 on Nucleosil 100-10 C18 column). The fractions containing ((1S,2R)-4-Amino-1-benzyl-2-hydroxy-butyl)-carbamic acid tert-butyl ester are set to a basic pH by addition of soda and extracted with EtOAc. The organic layer is dried over sodium sulfate and concentrated under reduced pressure to give 682 mg of the desired product.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[C:12]=1[CH3:19]>O1CCOCC1.O>[CH3:18][C:13]1[C:12]([CH3:19])=[C:11]([S:9][CH2:8][C:4]2[O:3][CH:7]=[CH:6][CH:5]=2)[CH:16]=[CH:15][N+:14]=1[O-:17]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: SCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(SCc2ccco2)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g of (60%) NaOH are added in portions to 50 ml of dry dioxane, the mixture is stirred for 15 minutes, 11.7 g (0.11 mol) of 2-furylmethylmercaptan are metered in, in the course of 20 minutes, and the mixture is again stirred for 30 minutes until the evolution of gas has ceased. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of dioxane is subsequently added dropwise in the course of 20 minutes, the reaction mixture is stirred at RT for 1 h, subsequently at 70° C. for 1 h and thereupon at 100° C. for a further 1 h. After the reaction has ended, the mixture is allowed to cool, diluted with 500 ml of water and extracted 4 times using in each case 300 ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate, concentrated and crystallized by adding diisopropyl ether. This gives 18.8 g (80% of theory) of 2,3-dimethyl-4-(2-furylmethylthio)pyridine N-oxide of m.p. 111°-112° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:11][C@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@H:12]([NH:11][C:8]([C:6]3[N:7]=[C:3]([NH:2][CH3:1])[S:4][CH:5]=3)=[O:10])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CNc1nc(C(=O)O)cs1
Product: CNc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 9.08 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(methylamino)thiazole-4-carboxylic acid (0.34 g, 2.149 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.467 g, 1.791 mmol). The product was purified by Flash-chromatography. Yield 9.08%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 2.85 (d, 3H), 4.30-4.42 (m, 3H), 6.96 (d, 1H), 7.18 (d, 1H), 7.59 (d, 1H), 7.84 (d, 1H), 7.91 (d, 1H), 7.95-7.96 (m, 2H), 8.08 (dd, 1H).