Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O-])(=O)=O.[C:6]([CH2:8][C@H:9]([NH3+:12])[CH2:10][CH3:11])#[N:7].CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>ClCCl>[CH:26]([O:25][C:23](=[O:24])[NH:12][C@H:9]([CH2:10][CH3:11])[CH2:8][C:6]#[N:7])([CH3:28])[CH3:27]
Reactant: CC[C@@H]([NH3+])CC#N
Reactant: CC(C)OC(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CC#N)NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of (R)-2-cyano-1-ethylethylammonium methanesulfonate (50 mmol; 9.72 g) and DIPEA (105 mmol; 13.6 g) in dichloromethane (100 mL) is added isopropyl chloroformate (52.5 mmol; 6.43 g) at 0° C. The solution is warmed to room temperature and stirred for 4 hours. The reaction mixture is quenched with brine and extracted with dichloromethane. The organic layer is washed with aqueous 0.1M HCl, saturated aqueous NaHCO3 solution and then brine, dried over MgSO4, filtered concentrated under reduced pressure to give ((R)-2-cyano-1-ethyl-ethyl)-carbamic acid isopropyl ester (8.75 g, 95%); ESI-MS m/z: 185 [M++1], Retention time 1.60 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([N:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:22][C@H:23]5[C@@H:24]([C:30](=[O:31])[NH2:32])[C@H:25]6[CH2:29][C@@H:28]5[CH:27]=[CH:26]6)=[C:4]4[N:10]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Product: CCNC(=O)N1CCC(n2cc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cn2)CC1

Procedure:
In a similar fashion as for the synthesis of Compound LXI, (1S,2S,3R,4R)-3-[6-Chloro-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was reacted with ethyl isocyanate to afford the title compound as a white lyophilate (70%). 1H NMR (d-chloroform): 8.36 (d, J=8 Hz, 1H), 8.11 (s, 2H), 7.87 (s, 1H), 6.47 (m, 1H), 6.42 (m, 1H), 5.81 (br s, 1H), 5.45 (br s, 1H), 5.36 (m, 1H), 4.42 (m, 2H), 4.15 (m, 2H), 3.33 (m, 2H), 3.17 (s, 1H), 3.02 (m, 3H), 2.67 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 2.23 (m, 2H), 2.10 (m, 3H), 1.69 (d, J=8 Hz, 1H), 1.20 (t, J=9 Hz, 1H). MS: 524.21 (M+H). HPLC retention time: 1.96 minutes (G Method).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH2:19])([CH2:12]3)[CH2:10]1)[CH2:16]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH:19][C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[O:27])([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: O=C(O)c1ccccn1
Reactant: NC12CC3CC(C1)CC(C#Cc1cnccn1)(C3)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC12CC3CC(CC(C#Cc4cnccn4)(C3)C1)C2)c1ccccn1
Temperature: 25 °C
Yield: 116.2 %

Procedure:
To a solution of intermediate 11, 3-(pyrazin-2-ylethynyl)-1-adamantylamine (30 mg, 0.12 mmol) and picolinic acid (18 mg, 0.15 mmol) in DMF (2 mL) was added DIEA (50 mg, 0.38 mmol) and HATU (60 mg, 0.12 mmol) under N2. After stirring at room temperature for an hour, the reaction was quenched with brine and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by Prep HPLC to give 50 mg (95%) of the title compound, pyridine-2-carboxylic acid (3-pyrazin-2-ylethynyl-adamantan-1-yl)-amide, as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.60-8.43 (m, 4H), 8.17 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.85-7.82 (m, 1H), 7.42-7.39 (m, 1H), 2.45 (s, 2H), 2.26-2.20 (m, 4H), 2.11-1.97 (m, 6H), 1.76-1.69 (m, 2H); ESI-MS m/z: 359 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]=O)[CH2:3][CH2:2]1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O1CCOCC1.[Ni]>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:11]([CH2:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:16][CH2:17]1
Reactant: O=CCCN1CCOCC1
Reactant: NCCCN1CCOCC1
Agent: [Ni]
Solvent: C1COCCO1
Product: C(CN(CCCN1CCOCC1)CCCN1CCOCC1)CN1CCOCC1

Procedure:
143 g (1 mol) of 3-morpholinopropionaldehyde in 143 g of dioxane are pumped into 72 g (0.5 mol) of aminopropylmorpholine and 30 g of Raney nickel at 120° C. and hydrogenated at 180 bar.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:19]1[N:18]([CH3:17])[CH:22]=[CH:21][CH:20]=1
Reactant: Cn1cccc1C=O
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Cn1cccc1CNCCNc1ccc2ccccc2c1Cl
Yield: 47 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and 1-methyl-1H-pyrrole-2-carbaldehyde in 47% yield as a white oil.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:10]1([NH:13][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)NC1CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 46.7 %

Procedure:
To a 250 mL of sealed tube was added ethyl 2-bromo-2-methylpropanoate (19.4 g, 0.1 mol, 1.0 equiv), cyclopropanamine (11.4 g, 0.2 mol, 2.0 equiv), K2CO3 (27.6 g, 0.2 mol, 2.0 equiv), KI (1.66 g, 0.01 mol, 0.1 equiv) and 200 mL of MeCN. The mixture was stirred at 100° C. for 12 h then cooled to room temperature and the solids were filtered. The filtrate was concentrated and purified on silica gel column eluting with pet. ether/ethyl acetate=4/1 to give 8.0 g (46%) of ethyl 2-(cyclopropylamino)-2-methylpropanoate.
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.[Na].[Si:9](Cl)([CH3:12])([CH3:11])[CH3:10].Cl>COCCOCCOC.O>[Si:9]([CH2:7][CH:1]([Si:9]([CH3:12])([CH3:11])[CH3:10])[Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na]
Solvent: COCCOCCOC
Solvent: O
Product: C[Si](C)(C)CC([Si](C)(C)C)[Si](C)(C)C
Temperature: 115 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
In a 500 ml three-necked standard taper joint round-bottomed flask were combined 12.2 g (0.53 mol) of Na metal chunks and 201.8 g of anhydrous diglyme. Flask was fitted with an electric heating mantle, mechanical stirrer (stainless steel blade), addition funnel, Dewar condenser (containing toluene cooled by immersion coil through which ice water was circulated), thermometer, and valves to maintain an inert atmosphere (nitrogen). Heat was applied, melting the sodium, and addition of a mixture of 54.8 g (0.5 mol) of Me3SiCl and 24.3 g (0.24 mol) of CH2 =CHSiMe3 begun at 115°, and continued, with continuous heating, at a rate which maintained the reflux temperature above 98°. Heating at reflux (115° C.) continued for 8 hr, and standing at room temperature for 32 hr, followed by termination by slow addition of a solution of 16.0 g H2O in 57.7 g diglyme and neutralization with 5 g conc HCl in 26.8 g diglyme. Salts were removed by filtration, and the organic layer vacuum distilled, yielding 4.65 g (7.9%) of Me3SiCH2CH(SiMe3)2, identified by VPC/NMR, plus 39.6% of Me3SiOSiMe3 and 6.2% of Me3SiSiMe3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]#[N:13])[CH:8]=[C:7]2[S:14]([CH3:17])(=[O:16])=[O:15].[CH2:18](N)[CH2:19][NH2:20]>C(=S)=S>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[NH:20][CH2:19][CH2:18][N:13]=1)[CH:8]=[C:7]2[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cn(CC#N)c2c(Cl)cccc12
Reactant: NCCN
Solvent: S=C=S
Product: CS(=O)(=O)c1cn(CC2=NCCN2)c2c(Cl)cccc12
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
(7-chloro-3-methanesulfonyl-indol-1-yl)-acetonitrile (2.1 g) from Step 7 was dissolved in ethylene diamine (10 ml) and 2 drops of carbon disulfide were added. The flask was blanketed with nitrogen and then placed in an oil bath previously heated to 140° C. The mixture was stirred and after 30 minutes checked by mass spec which revealed the complete absence of starting material and the appearance of the desired product (positive ion spectrum) as well as an undetermined amount of unalkylated impurity from the previous reaction (negative ion spectrum). After 45 minutes, the reaction was cooled to room temperature and then placed in an ice bath. The product crystallized. Ethyl acetate (10 ml) was added and the precipitate was broken up, filtered, and then washed with a bit of ethyl acetate followed by ether. Air drying gave 1.22 g of a colorless crystalline solid, 7-chloro-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indole which after vacuum drying overnight at 60° C. weighed 1.21 g. The material was analytically pure.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Br:33][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: NC[C@@H](O)c1cccc(Br)c1
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Br)c2)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-bromo-phenyl)-ethanol hydrochloric acid salt (96 mg, 0.37 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (73 mg, 63%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.21–7.40 (m, 5H), 6.14 (d, J=7.5 Hz, 1H), 4.97 (m, 1H), 3.60–3.68 (m, 2H). LCMS (t=1.46 min), [M+H]+465.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:35])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11]([CH2:19][C:20]2[N:21]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)=[C:10]1[CH3:34])C.Cl>O1CCCC1.O>[C:28]1([S:25]([N:21]2[CH:22]=[CH:23][CH:24]=[C:20]2[CH2:19][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:9]([CH2:8][C:7]([OH:35])=[O:6])[C:10]=2[CH3:34])(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2cccn2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2cccn2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Lithium hydroxide monohydrate (138 mg, 3.3 mmol) was added in one portion to a stirred solution of [3-(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid ethyl ester (507 mg, 1.1 mmol) in tetrahydrofuran:water (2:1; 10 ml) and the resulting mixture stirred at room temperature for 3 h. The solution was adjusted to pH 1 with 1M hydrochloric acid and then concentrated in vacuo to leave a yellow solid. The solid was partitioned between ethyl acetate (30 ml) and water (30 ml) and then the organic layer separated. The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were then dried and concentrated in vacuo to leave an off-white solid. Purification by flash column chromatography on silica gel eluting with 10% methanol:dichloromethane gave the carboxylic acid (130 mg, 28%) as a white solid, δH (250 MHz, d6-DMSO) 7.84 (2H, d J 7.1 Hz, Ar), 7.74 (1H, d J 7.1 Hz, Ar), 7.65-7.59 (2H, m, Ar), 7.44-7.41 (1H, m, Ar), 7.35-7.30 (1H, m, Ar), 6.82 (1H, td J 9.3, 2.4 Hz, Ar), 6.42 (1H, dd J 9.8, 2.4 Hz, Pyrrole-CH), 6.23-6.21 (1H, m, Pyrrole-CH), 5.56 (1H, br s, Pyrrole-CH), 4.94 (2H, s, CH2-Pyrrole), 4.02 (2H, s, CH2CO2H), 2.52 (3H, masked s, CCH3); Tr=1.63, m/z (ES+) (M+H)+ 427.19.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:19]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: NCc1ccccc1Cl
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: Clc1ccccc1Cn1cnnc1-c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 2-chlorobenzylamine (0.5 ml) as described above; yield: 0.089 g (28.8%);
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:16]([CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
To a suspension solution containing 4.4 g of 60% NaH in 200 ml of THF, 17.8 g of ethyl 3-phenylpropionate and 8.2 g of ethyl formate were added dropwise under ice cool for one hour. Thereafter, the mixture was stirred at room temperature for 15 hours. Furthermore, 14 g of 60 % NaH and 25.9 g of ethyl formate were divided into three parts and each part was added separately. Afterwards, the solution mixture was stirred at room temperature for 15 hours. After a 10% citric acid solution was added to the resultant reaction solution, the reaction solution was extracted with ethyl acetate and the extract was concentrated under reduced pressure to obtain 32.4 g of a brown oily concentrate. The concentrate thus obtained was purified by silica gel column chromatography to obtain 17.9 g of the titled compound as a transparent oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([NH:13][CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12].CO.[BH4-].[Na+]>O>[CH2:10]([N:13]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12]
Reactant: O=Cc1ccccc1O
Reactant: C=CCNCC=C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCN(CC=C)Cc1ccccc1O
Temperature: 0 °C
Yield: 64 %

Procedure:
12 g of 2-hydroxybenzaldehyde was placed in a 500 ml round bottom flask with 100 ml of diallyl amine and 100 ml of methanol. The reaction mixture was then cooled to 0° C. 4 g of NaBH4 (powder) was slowly added within 2.5 hrs and the temperature was kept at 0-6° C. Water was then added to the reaction mixture to terminate the reaction. The reaction mixture was then concentrated, and extracted with ethyl acetate and water. The organic phase was collected and concentrated to obtain crude product. The obtained crude product was eluted and purified with mobile phase eluant of n-hexane:ethylacetate (EA)=4: 1 and solid phase of silica gel. 12.8 g of the product of formula (IX) was obtained and recovery yield was 64%.
Reaction SMILES: [NH2:1][OH:2].C(N(CC)CC)C.[C:10]([O:14][C:15]([O:17]C([O-])=O)=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:15]([NH:1][OH:2])([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:17]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 362 %

Procedure:
To a solution of amino alcohol from Step 3 (2.60 g, 5.81 mmol) in DCM (60 mL) was added triethylamine (1.60 mL, 12.0 mmol) followed by tert-butyldicarbonate (1.50 g, 6.88 mmol) and the reaction was stirred overnight at RT. The final mixture was concentrated and purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 80:20 to 20:80) to provide 2.80 g (88%) of Boc-amino alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([CH3:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:18])[CH:3]=[C:2]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: Cc1cc(Cl)nc(N[C@@H](C)c2ccc(F)cc2)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
95 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-methylpyridine-2-amine, 40 mg of 2-aminopyrazine, 34 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 48 mg of sodium t-butoxide and 19 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 85 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-methyl-N6-(pyrazin-2-yl)pyridine-2,6-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 38 mg of the objective compound as yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:34])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)N(C)CCC1.O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CN(S(=O)(=O)c2ccc(F)cc2)C1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)C(=O)OC(C)(C)C)C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
To a solution of Benzyl-[1-(4-fluoro-benzenesulfonyl)-azetidin-3-yl]-carbamicacid tert-butyl ester (0.21 g, 0.5 mmol) in N,N′-dimethylpropyleneurea (0.5 ml) was added butylamine (0.15 g, 2 mmol) and potassium carbonate (0.07 g, 0.5 mmol), and the mixture was stirred at 50° C. for 2 days. It was then cooled to room temperature and diluted with water (20 ml). The aqueous phase was removed, and the residue dissolved in ether (20 ml). The ether solution was washed with 0.5 N HCl, saturated sodium bicarbonate solution, and brine, and dried over anhydrous sodium sulfate. It was then filtered through a pad of silica gel. The filtrate was evaporated, and the residue was triturated with hexanes to give 0.23 g of a white solid; m.p. 115-116° C.; MS (ES) m/z 474.1 (MH+); HRMS (El) Calcd. for C25H35N3O4S (M+): 473.2348, Found: 473.2338.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:10]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)c2ccncc2)c1=O

Procedure:
Using the method described in Example 14 from 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile and isonicotinic acid: isonicotinic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester was obtained as a light yellow solid (43.6 mg, 23%); ES+-HRMS m/e calcd for C24H17N7O6Cl2 (M+H+) 570.0690, found 570.0686.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:31]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][N:11]([CH3:31])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCNCC3)c21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cnn(C)c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-1-methyl-5-(trifluoromethyl)-1H-indazole (35 mg, 0.083 mmol) and sodium cyanoborohydride (10.4 mg, 0.166 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (42%). 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.29 (s, 1H), 7.14 (m, 2H), 6.87 (m, 2H), 4.68 (s, 2H), 3.98 (s, 3H), 3.44 (s, 2H), 2.50 (m, 2H), 2.00-2.25 (m, 7H), 1.91 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.2, 160.2, 139.4, 133.9, 128.62, 128.56, 124.8, 124.6 (q, J=272 Hz), 124.5 (q, J=2.9 Hz), 122.6 (q, J=33 Hz), 121.1, 119.7 (q, J=4.8 Hz), 115.0, 114.9, 78.7, 70.5, 51.8, 46.2, 40.2, 38.3, 32.6. Mass spec.: 436.15 (MH)+. Accurate mass spec.: m/z 436.2008 [MH]+, Δ=0.9 ppm.