Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=O.[CH3:27][NH:28][CH3:29].C1C(C(O)=O)=CC=C(NCC(NCC#N)=O)C=1>>[CH3:27][N:28]([CH2:1][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Reactant: CNC
Agent: N#CCNC(=O)CNc1ccc(C(=O)O)cc1
Product: CN(C)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate and dimethylamine as starting materials. LCMS (M+H-100)+: 405.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N:14]=[N+:15]=[N-:16])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH:17]1([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]2[CH:39]=[CH:38][O:37][CH:36]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:14]([C:9]1[CH:8]=[C:7]([CH2:6][C@H:2]([NH:1][C:32]([C:30]2[CH:29]=[CH:28][C:27]3[N:23]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:24]([C:35]4[CH:39]=[CH:38][O:37][CH:36]=4)=[N:25][C:26]=3[CH:31]=2)=[O:33])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][C:10]=1[OH:13])=[N+:15]=[N-:16]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: [N-]=[N+]=Nc1cc(C[C@H](N)C(=O)O)ccc1O
Product: [N-]=[N+]=Nc1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)ccc1O

Procedure:
To a solution of 3-amino-L-tyrosine.2HCl.H2O (2.50 g, 8.8 mmol) in 0.5 N HCl (28 mL) at 0° C., an aqueous solution of NaNO2 (0.724 g, 10.5 mmol, in 10 mL H2O) was added slowly. The reaction mixture was stirred for 10 min at 0° C., in the dark, and then a solution of NaN3 (1.43 g, 21.9 mmol, in 10 mL H2O) was added and stirring was continued for 1 h at 0° C. The white solid formed was filtered and dried to give (S)-2-amino-3-(3-azido-4-hydroxy-phenyl)-propionic acid (1.16 g) as of a beige solid. This amino acid was coupled to the carboxylic acid of example 2 in the usual manner to give the title compound of example 146 after purification by preparative C18 reversed-phase HPLC.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(C3(C(NC4C=CC(Br)=CN=4)=O)CC3)=CC=2OC1.[Cl-].[Cl:52]C1C=CC=CC=1C[Zn+]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:52])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ccccc1C[Zn+]
Reactant: O=C(Nc1ccc(Cc2ccccc2)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1ccc(Cc2ccccc2Cl)cn1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(2-chlorobenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-benzylpyridin-2-yl)cyclopropanecarboxamide by reacting 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyridin-2-yl)cyclopropanecarboxamide with (2-chlorobenzyl)zinc(II) chloride.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:50])[N:14]([CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([CH:48]=O)[CH:39]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36].[C:51]([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:50])[N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[CH2:37][C:38]1[CH:39]=[C:40]([CH:48]=[CH2:51])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1
Reactant: O=C([O-])O
Reactant: COC(=O)N(Cc1cc(C=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)C(=O)OC)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A suspension of Ph3PCH3Br (53.4 mg, 0.15 mmol) in THF (500 μL) was cooled to 0° C. potassium bis(trimethylsilyl)amide (256 μL of a 0.5 M solution in toluene, 0.128 mmol) was added slowly and the reaction was kept at 0° C. After fifteen minutes, methyl[3-formyl-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (24.2 mg, 0.043 mmol) (Example 40) was dissolved in THF (1 mL) and was added via cannula to the reaction which was then slowly warmed to room temperature. After fifteen minutes at room temperature, the reaction was diluted with EtOAc (30 mL), and poured into NaHCO3 (10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 25% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(trifluoromethyl)-5-vinylbenzyl]carbamate. Rf=0.42 (25% EtOAc/hexanes) LCMS=566.2 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.68 (broad singlet, 1H), 7.36 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.15 (broad singlet, 1H), 7.10 (d, J=10.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H), 6.32-6.27 (m, 1H), 5.40 (d, J=18 Hz, 1H), 4.97 (d, J=11 Hz, 1H), 4.37 (broad singlet, 2H), 4.04 (broad singlet, 2H), 3.34 (s, 3H), 3.20 (s, 3H), 2.69 (m, 1H), 1.12 (d, J=7.0 Hz, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(O)C>[ClH:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2c1[nH]c1ccccc12
Agent: Cl
Solvent: CCO
Product: Brc1cccc(Nc2ncnc3c2[nH]c2ccccc23)c1
Yield: 76.7 %

Procedure:
4-Chloroindolo[3,2-d]pyrimidine hydrochloride (240 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated at reflux under a nitrogen atmosphere for 2h. Filtration and washing of the collected solids with ethanol, followed by recrystallization from DMF gives 4-(3-bromoanilino)indolo[3,2-d]pyrimidine hydrochloride (288 mg, 77%). 1H NMR (DMSO) δ12.73 (1H, s), 11.42 (1H, s), 9.02 (1H, s), 8.41 (1H, s), 8.28 (1H, d, J=7.9 Hz), 7.95-7.92 (1H, m), 7.84-7.82 (1H, d, J=8.6 Hz), 7.74-7.69 (1H, m), 7.40-7.47 (3H, m). ##STR28##
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:12][CH3:13])[C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[NH3:14]>CO>[NH2:1][C:2]1[N:3]=[C:4]([O:12][CH3:13])[C:5]([C:8]([NH2:14])=[O:9])=[N:6][CH:7]=1
Reactant: N
Reactant: COC(=O)c1ncc(N)nc1OC
Solvent: CO
Product: COc1nc(N)cnc1C(N)=O

Procedure:
In 100 mL of methanol is suspended 1.96 g of methyl 5-amino-3-methoxy-2-pyrazinecarboxylate obtained according to the method described in literature (JP-A-50-105675). The resulting suspension is saturated with ammonia by introducing gaseous ammonia thereinto at −20° C. Then, the solution thus obtained is allowed to react at 95° C. for 24 hours in a stainless steel-made closed vessel. After cooling, the solvent is distilled off under reduced pressure to obtain 1.57 g of 5-amino-3-methoxy-2-pyrazinecarboxamide.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.BrN1[C:19](=[O:20])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][O:20][CH3:19])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1coc2c(Br)cc(F)c(F)c12
Yield: 41 %

Procedure:
To the compound (49.4 mg, 0.200 mmol) of Step 1 of Example 21, N-bromosuccinimide (hereinafter, NBS) (39.2 mg, 0.220 mmol), and a catalytic amount of benzoyl peroxide (hereinafter, BPO), carbon tetrachloride (2 mL) was added, and heated under reflux overnight. After the resultant was returned to room temperature, the insoluble material was filtered off. The solvent was distilled away under reduced pressure. The resulting residue was dissolved in methanol (2 mL), and a 25% sodium methoxide methanol solution (0.2 mL) was added thereto and heated under reflux for 3 hours. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. To the resulting residue, 1 N hydrochloric acid (1 mL) and a saturated aqueous ammonium chloride solution were added, and extraction was performed with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1)([O-])=O.[N+]([C:42]1[CH:55]=[CH:54][C:53]2[C:52](=[O:56])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45](=[O:57])[C:44]=2[C:43]=1[N+:58]([O-])=O)([O-])=O>>[N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:58][C:43]1[C:44]2[C:45](=[O:57])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52](=[O:56])[C:53]=2[CH:54]=[CH:55][CH:42]=1
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
The nitroanthraquinone used was composed of 69.1% of 1-nitroanthraquinone, 0.7% of 2-nitroanthraquinone and 26.8% of dinitroanthraquinone, and the 1-aminoanthraquinone content in the effluent aminoanthraquinone dry cake was 73.6%. The reduction yield from 1-nitroanthraquinone to 1-aminoanthraquinone was 99.7%. The crystals of the aminoanthraquinones obtained in this and following Examples 2-6 are represented by FIG. 2. They had excellent filterability as tested by a rotary vacuum filter or a pressure filter and could be efficiently separated from waste water of reduction.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12]
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)NS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a solution of ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (90 mg, 0.195 mmol) in DCM (3 ml) at room temperature is added TFA (1 ml, 12.98 mmol). The reaction is stirred at room temperature. The mixture is concentrated to give N-((2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoyl)-methanesulfonamide. Next, this crude is added a half solution of 2-benzyl-2H-tetrazole-5-carbonyl chloride (131 mg, 0.588 mmol) in DCM at 0° C. and is followed by half of TEA (0.109 mL, 0.782 mmol). And then after half hour, the other half reagents are added into the reaction. The reaction is warmed up slowly to room temperature. The reaction is quenched by brine and is extracted with DCM. The combined organic layer i washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 50% ACN—H2O (0.1% NH4OH) over 10 min by X-bridge phenyl column] provides 2-Benzyl-2H-tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. HPLC retention time=1.50 minutes (condition C), MS (M−1)=545.3.
Reaction SMILES: [NH2:1]CC(O)=O.[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH3:19])[CH:12]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH2:17]([C:13]1[CH:12]=[C:11]([N:10]([CH2:9][C:8]([O:7][CH3:6])=[O:20])[NH2:1])[CH:16]=[CH:15][CH:14]=1)[CH2:18][CH3:19]
Reactant: CCCc1cccc(NCC(=O)OC)c1
Reactant: NCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1cccc(N(N)CC(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Glycine (Intermediate 32, 10 g, 48 mmol) was dissolved in acetic acid (50 ml) and water (5 ml). The solution was cooled to 0° C. and sodium nitrite (3.67 g, 53 mmol) in water (10 ml) was added such that the temperature did not rise above 5° C. The yellow solution turned red then brown, and was stirred at 0° C. for 1 h. The mixture was cooled to -5° C. and zinc powder (12.6 g, 193 mmol) was added very slowly such that the temperature did not rise above 0° C. The mixture was stirred at 0° C. for 5 h then poured into water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined, dried (Na2SO4) organic extracts were concentrated in vacuo to give a dark yellow oil. The crude material was purified by chromatography on silica (500 g) eluted with chloroform-ethanol 98:2 to give the title compound (Intermediate 33, 1.4 g, 13%) as a yellow oil.
Reaction SMILES: F.F.F.[CH3:4][N:5]([CH3:36])[O:6][CH2:7][CH2:8][O:9][C@:10]1(CCN)[C@:14](CCN)([OH:15])[C@@H:13]([CH2:19][OH:20])[O:12][C@@:11]1(CCN)[N:21]1[CH:28]=[C:27]([CH3:29])[C:25](=[O:26])[NH:24][C:22]1=[O:23].C(N(CC)CC)C.[Si](OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)[C@H](OCCON(C)C)[C@@H]1O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:4][N:5]([CH3:36])[O:6][CH2:7][CH2:8][O:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:19][OH:20])[O:12][C@H:11]1[N:21]1[CH:28]=[C:27]([CH3:29])[C:25](=[O:26])[NH:24][C:22]1=[O:23]
Reactant: Cc1cn([C@]2(CCN)O[C@H](CO)[C@](O)(CCN)[C@@]2(CCN)OCCON(C)C)c(=O)[nH]c1=O
Agent: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.2 %

Procedure:
2'-O-(dimethylaminooxyethyl)-5-methyluridine Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5'-O-tert-butyldiphenylsilyl-2'-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2'-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)=[CH:21][CH:20]=1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 4-fluorobenzylamine (70 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (20 mg) and a syn-form compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.C(N(CC)CC)C.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)[C@@H](CNC(=O)C(F)(F)F)C2
Reaction time: 2 h

Procedure:
To 2.9 g (15 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine in 7.5 mL of methanol, at ambient temperature, there are added, all at once, 2.1 mL (15 mmol/1 eq.) of triethylamine, and then, dropwise, over 20 minutes, 2.3 mL (19 mmol/1.25 eq.) of ethyl trifluoroacetate. Stirring is carried out at ambient temperature for 2 hours, followed by evaporating to dryness. The residue is taken up in 100 mL of dichloromethane, and washing with 50 mL of 1N hydrochloric acid and then 50 mL of water and drying over magnesium sulphate are carried out. After filtration and concentration, the desired product is collected.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][CH:14]([NH:19][CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH2:24]=O>C(O)=O>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([N:19]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH3:24])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: C=O
Reactant: Brc1csc2ncnc(N3C4CCC3CC(NC3CCC3)C4)c12
Solvent: O=CO
Product: CN(C1CCC1)C1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Yield: 81 %

Procedure:
8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine (200 mg, 0.5 mmol) in formalin solution (5 mL) and formic acid (5 mL) was heated to 80° C. for 1 h. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (50 mL) and 10% potassium carbonate solution (10 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give a colourless gum. The gum was chromatographed on a 25 g silica column in a gradient of 2-15% methanol in dichloromethane. The slower running peak was collected to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-N-methyl-8-azabicyclo[3.2.1]octan-3-amine (165 mg, 0.405 mmol, 81%). 1H NMR (CDCl3) δ: 1.35 (2H, t, J=12 Hz), 1.5-1.7 (4H, m), 1.8-2.0 (6H, m), 2.1 (3H, s), 2.5 (2H, br m), 3.1 (2H, br m), 4.7 (2H, br m), 7.3 (1H, s), 8.4 (1H, s).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH3:7]>C(Cl)(Cl)Cl>[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][CH:17]=[C:16]2[S:2]([OH:5])(=[O:4])=[O:3])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)c1ccc(-n2cccc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(-n2cccc2S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Chlorosulfonic acid (1.82 ml, 27.08 mmol) was slowly added to a solution of 1-(4′-isopropylphenyl)pyrrole (5.01 g, 27.08 mmol) in chloroform (100 ml) at 0° C. The resulting solution was stirred at 0° C. for 1 h and for an additional 1 h at room temperature. Chloroform was removed under reduced pressure. The resultant brown liquid was diluted with ethyl acetate (200 ml) and washed with 1 N sodium hydroxide. The aqueous layer was then acidified with concentrated hydrochloric acid (pH<1) and then extracted with chloroform (2×150 ml). The combined organic layers was dried over magnesium sulfate and was filtered. Removal of the solvent gave 1-(4′-isopropylphenyl)pyrrole-2-sulfonic acid as a brown syrup (3 g, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:6]#[N:7].[NH2:17][N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=O.CC(C)([O-])C.[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:7]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)[CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C#N)ccc1-c1ccccn1
Reactant: Nn1ccccc1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COc1cc(-c2nc3ccccn3n2)ccc1-c1ccccn1
Temperature: 115 °C

Procedure:
3-methyoxy-4-pyridin-2-ylbenzonitrile (104 mg, 0.95 mmol) and 1-aminopyridin-2(1H)-one (198 mg, 0.95 mmol) were dissolved in a solution of potassium t-butoxide (2 mL of 1M in t-butanol, 2.0 mmol). The reaction mixture was heated to 115° C. for 1 h, cooled and concentrated. The residue was purified by flash column chromatography on silica gel eluting with MeOH:CH2Cl2 (1:19) to afford the desired 2-(3-methoxy-4-pyridin-2-ylphenyl)[1,2,4]triazolo[1,5-a]pyridine. 1H NMR (CDCl3, 300 MHz) δ 8.75 (m, 1H), 8.64 (d, 1H), 8.06 (dd, 1H), 7.97 (s, 1H), 7.94 (m, 2H), 7.81 (d, 1H), 7.74 (dt, 1H), 7.55 (m, 1H), 7.25 (m, 1H), 7.05 (dt, 1H), 4.03 (s, 3H) ppm. 3C NMR (CDCl3, 75 MHz) δ 163.8, 157.2, 155.5, 151.7, 149.4, 135.7, 132.2, 131.5, 130.6, 129.6, 128.3, 125.2, 121.9, 120.0, 116.4, 113.8, 110.0, 55.8 ppm. MS (ESI) 303 (M)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:21])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Yield: 37.5 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (9.4 g, 39 mmol) was dissolved in anhydrous 1,2-dichloroethane and stirred under N2(g) atmosphere. To the mixture was added POCl3 (29 mL, 312 mmol), followed by N,N-dimethylaniline (4.75 g, 39 mmol). The mixture was refluxed for 2 h and the solvents were removed under vacuum to give a red residue. The residue was dissolved in 20 mL of ethyl acetate and 20 ml of water was added. The solution was neutralized with ice and solid NaHCO3. After neutralization, ethyl acetate was added and the organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and the solvents were removed under vacuum. The resulting red residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as yellow crystals (3.8 g, 38%).