Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:7][N:6]=1.[Br:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].O>CN(C)C=O>[Br:26][C:27]1[CH:34]=[C:33]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:13]3[C:5]([C:4]([F:24])([F:3])[F:25])=[N:6]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1Br
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Sodium hydride (0.183 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (1d) (0.940 g) in N,N-dimethylformamide (hereinafter referred to as DMF, 6 mL) at room temperature, followed by stirring for 30 min. Subsequently, 2-bromo-4-fluorobenzonitrile (0.838 g) was added to the reaction solution, followed by stirring at 60° C. for 1 hr. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1e) (0.56 g, 38%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[S:8][C:6]=2[N:7]=1.[CH3:17][NH:18][CH3:19].CO>>[CH3:17][N:18]([CH3:19])[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[S:8][C:6]=2[N:7]=1
Reactant: CNC
Reactant: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Solvent: CO
Product: CCOC(=O)Nc1nc2cnc(N(C)C)nc2s1
Temperature: 75 °C
Yield: 99 %

Procedure:
Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg, 1.16 mmol) was suspended in a 2.0 M solution of dimethylamine in methanol (5.0 mL, 10.00 mmol) in a pressure vessel, which was sealed and heated overnight on a 75° C. oil bath. The mixture was cooled to ambient temperature, the solvent was evaporated and the residue was partitioned between aqueous bicarbonate and chloroform and extracted 3 times. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbamate (236 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H) 8.67 (s, 1H) 4.26 (q, J=7.03 Hz, 2H) 3.17 (s, 6H) 1.16-1.40 (m, 3H). MS (LC/MS) R.T.=1.88; [M+H]+=268.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3cccc(F)c3)c2c1
Yield: 16.7 %

Procedure:
A solution of {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (68.3 mg, 0.162 mM) and 0.81 mL (1.6 mM) of 2 N NaOH in 8.1 mL of ethanol was stirred for 30 minutes at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 11 mg (16%) of {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. The filtrate was acidified with 1N HCl to pH=2. After cooling to 5° C., the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 31 mg (47%) {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ 7.75 (bs, 1H), 7.6 (d, 1H, J=8 Hz), 7.45 (bs, 1H), 7.4-7.25 (m, 2H), 7.05 (m, 3H), 6.95 (d, J=8 Hz, 1H), 6.9 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 4.8 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 390, 407. Recrystallization from acetone/hexane provided an analytical sample:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[CH:34][C:29]4[NH:30][C:31]5[C:27]([CH:28]=4)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:33][CH:32]=5)[C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
A mixture of 6-phenyl-2-oxindole (41 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (72%) of the title compound as a red solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[CH2:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccccc5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccccc5)n4)n[nH]c3n2)CC1

Procedure:
To a solution of {4-[3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (22 mg, 0.043 mmol) in methanol (30 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was then concentrated by evaporation to afford N-[3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-cyclohexane-1,4-diamine; hydrochloride. (Yield 20 mg, 90.9%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[CH:11]([OH:13])[CH3:12].[CH2:14]([OH:16])[CH3:15]>[Fe]>[C:14]([O:13][CH:11]([C:4]1[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[Cl:2])[CH3:12])(=[O:16])[CH3:15]
Reactant: CCO
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Product: CC(=O)OC(C)c1c(Cl)ccc(F)c1Cl
Temperature: 85 °C

Procedure:
2 M HCl (0.2 mL) is added to solution of compound A1 (0.97 mmol) in 2 mL of ethanol. The mixture is then put in an ice bath and Fe powder (365 mg) is added slowly. The reaction is heated to 85° C. for 1 hr and cooled to room temperature. Celite (0.5 g) is added to stir and the resulting mixture is filtered through a bed of celite and rinsed with ethanol. The filtrated is evaporated to give a brown oil residue, compound A2. The residue is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[S:17][C:10]=12.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:45])[CH2:41][C:42](O)=[O:43].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:42](=[O:43])[CH2:41][C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[O:45])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
To a solution of amine 54 (260 mg, 0.57 mmol, crude) in DMF (6 mL), were added acid 27 (108 mg, 0.52 mmol) and HOBt (77 mg, 0.57 mmol). After stirring for 5 min, EDC (120 mg, 0.63 mmol) was added, and the reaction mixture was stirred at room temperature for additional 4 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Aquasil C-18, gradient, MeOH 60% to MeOH 95% in water) to afford title compound 48 (160 mg, 46% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.87 (bs, 1H), 10.75 (s, 1H), 9.62 (s, 1H), 8.60 (d. 1H), 8.17 (s, 1H), 8.02 (m, 3H), 7.89 (d, 1H), 7.74 (d, 2H), 7.51 (m, 1H), 7.05 (m, 2H), 6.90 (t, 1H), 6.79 (d, 1H), 4.39 (d, 1H), 6.57 (d, 1H), 3.84 (s, 2H), 3.69 (s, 2H), 3.35 (m, 2H), 3.06 (m, 3H), 2.00 (m, 2H), 1.87 (m, 2H). MS (m/z): 610.0 (M+H).
Reaction SMILES: [CH:1]([NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH2:3][CH3:4])[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>O>[CH:1]([N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:26](=[O:27])[CH2:25][Cl:24])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-Sec-Butyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.0 grams, benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (6.0 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-sec-butyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[CH3:15][NH:16][CH3:17].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([N:16]([CH3:17])[CH3:15])[N:3]=[C:4]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:5]=1
Reactant: CNC
Reactant: FC(F)(F)CNc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CC(C)=O
Product: CN(C)c1nc(Cl)nc(NCC(F)(F)F)n1
Yield: 93 %

Procedure:
14.8 g (0.06 mol) of 2,4-dichloro-6-(2,2,2-trifluoroethylamino)-s-triazine (prepared as described in Example 3) were dissolved in 100 ml of acetone, and 12 ml of an approximately 45% strength aqueous dimethylamine solution were added dropwise at room temperature. The temperature was kept below 30° C. by cooling with water. The reaction product was precipitated by further addition of water. 14 g (=93% of theory) of 2-chloro-4-dimethylamino-6-(2,2,2-trifluoroethylamino)-s-triazine were obtained; melting point 181° to 184° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1.Cl.[OH-].[Na+]>>[NH2:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N)cnc1Cl
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-3-methoxy-5-nitropyridine (1.5 g, 0.008 mole) was added to concentrated hydrochloric acid (15 ml) at 5° C., followed by stannous chloride (5.0 g). The reaction mixture was stirred for 10 minutes at 5° C., heated for 30 minutes on a steam bath, cooled, neutralized with aqueous sodium hydroxide (20 percent by weight) and extracted with 1,1,1-trichloroethane. The trichloroethane extract was dried over MgSO4 and evaporated in vacuo to yield a white solid; yield, 1.02 g (91 percent), m.p. 93° to 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17]C)[CH:16]=1)[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:6].B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:5]([N:7]([CH:8]([CH3:9])[CH3:10])[CH:11]([CH3:12])[CH3:13])=[O:6]
Reactant: COc1cc(Cl)cc(C(=O)N(C(C)C)C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(C(=O)c1cc(O)cc(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 79.8 %

Procedure:
To a stirred solution of 3-chloro-N,N-diisopropyl-5-methoxy-benzamide (2.96 g) in anhydrous dichloromethane (30 ml) at −78° C. was added boron tribromide solution in dichloromethane (40 ml). The reaction mixture was allowed to warm to ambient temperature and stirred for 19 h. The reaction mixture was cooled to −78° C. and methanol (20 ml) added. The reaction mixture was allowed to warm back to ambient temperature, stirred for 24 h, and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water and dried with brine and over sodium sulphate. The crude product was purified by flash column chromatography, eluting with cyclohexane:ethyl acetate (1:1), to give the title compound as a white solid (2.24 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(S(F)(F)[F:25])CC)C.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([F:25])[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Temperature: -45 °C
Yield: 64 %

Procedure:
A solution of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester prepared as described in Example 1 Part A(2) (6 g, 24.1 mmole) was dissolved in dichloromethane and cooled to -45° C. under an argon atmosphere. To the above solution diethylaminosulfur trifluoride (5.2 ml, 42 mmole) was added dropwise. The resulting solution was stirred and warmed to -35° C. To the above solution pyridine was added dropwise (9 ml, 116 mmole). The reaction was allowed to stir overnight while warming to room temperature. The solvent was removed in vacuo and the oily residue treated with ethyl acetate and 1N HCl. The mixture was transferred to a separatory funnel, the aqueous layer removed, and the organic layer washed with additional 1N HCl, then water and saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate, filtered and concentrated to a yellow oil. The crude product was chromatographed on silica gel using 1:1 ethyl acetate:hexane as eluent. Combination and concentration of product containing fractions produced 3.9 gm (64%) of title compound as an oil.
Reaction SMILES: [Br:1]CCCC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1.Cl[CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>>[Br:1][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(C#CCCCCl)cc1
Product: O=[N+]([O-])c1ccc(C#CCCCBr)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 40, using Intermediate 41 as a substrate. ES/MS calcd. for C11H11BrNO2+ 268.0. Found m/z=268.1 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]([OH:53])=[CH:41]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:41]2[C:40]3[C:45](=[CH:46][C:47]([O:48][CH3:49])=[C:38]([O:37][CH3:36])[CH:39]=3)[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]=2[OH:53])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]
Reactant: COCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(COC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (84 mg, 0.29 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol SMA 44012 (73 mg, 0.29 mmol) followed by a 2 N aq. LiOH solution (0.29 mL, 0.58 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL) and the mixture was stirred for 5 min at room temperature and concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol dihydrochloride 67 as a yellow solid (9 mg, 6% yield).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[OH:22][C:23]1[CH:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:29][C:27]5[CH:26]=[CH:25][NH:24][C:23](=[O:22])[CH:28]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: O=Cc1ccnc(O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: O=c1cc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc[nH]1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-hydroxypyridine-4-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 4-[[5-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]methyl]-1H-pyridin-2-one.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH2:32][O:33][CH3:34])=[CH:28][CH:29]=3)[O:24][CH2:23][C:22]2([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[CH3:35])(=O)=O)=CC=1.[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.[OH-].[Na+]>O1CCOCC1>[CH3:34][O:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]2[C:30]([CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:22]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=3)([CH3:35])[CH2:23][O:24]2)=[CH:29][CH:28]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCNCC2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
9-{7-(Methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman-4-yl}nonyl 4-methylbenzenesulfonate (540 mg, 0.843 mmol) and piperazine (2.2 g, 25.5 mmol) were dissolved in dioxane and then the mixture was refluxed for 2 hours. The mixture was cooled down to room temperature, basified to pH 13 using 5N-NaOH, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the organic solvent was removed under reduced pressure. The concentrate was subjected to column chromatography (methanol) to give 380 mg (yield: 81%, (3RS,4RS):(3RS,4SR)=5:4) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A solution of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (3.0 g, 10.54 mmol) and 4-azetidin-3-ylmorpholine (1.8 g, 12.66 mmol) in DCE (200 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (3.5 g, 16.5 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (50 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 99:1 to 98:2 to 95:5) to afford 4-(5-chloro-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine as a cream solid (2.66 g, 61%). LCMS (Method C): RT=2.68 min, [M+H]+ 411.3
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:14]=[C:13]([C:15]#[N:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:14]=1)#[N:16]
Reactant: CCOC(=O)c1ncc2c(cc(C#N)n2Cc2cccc(F)c2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc2c(O)c(C(=O)NCC(=O)O)ncc2n1Cc1cccc(F)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 2-cyano-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:24][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][OH:16]
Reactant: COCOc1cc(CO)cc(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(CO)c(Br)c(OCOC)c1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of (3,5-bis-methoxymethoxy-phenyl)-methanol (9.16 g, 40.2 mmol) in DMF (40 mL) was treated with NBS (7.51 g, 42.2 mmol) at room temperature and the mixture was stirred at same temperature for 30 min. The residue was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=1:1) to afford the title compound (10.2 g, 83%). 1H NMR (300 MHz, CDCl3) δ 6.91 (s, 1H), 6.81 (s, 1H), 5.24 (s, 2H), 5.17 (s, 2H), 4.72 (d, J=6.3 Hz, 2H), 3.52 (s, 3H), 3.47 (s, 3H), 2.05 (t, 1H).