Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25].[K+].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:22][C:19]1([CH3:23])[CH2:20][CH2:21][C:16]([C:3]2[CH:4]=[C:5]([CH2:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:2]=2[NH:1][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])=[CH:17][CH2:18]1
Reactant: CC1(C)CC=C(c2cc(CC(=O)NCCCO)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CC(=O)NCCCO)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)), PyBroP and DIEA according to the procedure in Example 1, step (f). 1H-NMR (CDCl3; 400 MHz): δ 9.74 (s, 1H), 8.31 (d, 1H, J=8.3 Hz), 7.78 (s, 1H), 7.20 (dd. 1H, J=8.4, 1.9 Hz), 7.11 (d, 1H, J=1.9 Hz), 7.03 (br s, 1H), 5.94 (s, 2H), 5.75 (s, 1H), 4.22 (t, 1H, J=6.1 Hz), 3.67-3.63 (m, 2H), 3.61-3.56 (m, 2H), 3.52 (s, 2H), 3.38-3.33 (m, 2H), 2.27-2.23 (m, 2H), 2.08-2.07 (m, 2H), 1.67-1.61 (m, 2H), 1.57 (t, 2H, J=6.2 Hz), 1.09 (s, 6H), 0.98-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[C:8]([C:6]1[CH:7]=[C:2]([C:24]2[C:19]([O:18][CH3:17])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]=1[O:12][CH3:13])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1cc([N+](=O)[O-])c(OC)c(C(C)(C)C)c1
Temperature: 115 °C
Yield: 81.8 %

Procedure:
step 1—A mixture of 5-bromo-1-tert-butyl-2-methoxy-3-nitrobenzene (0.48 g, 1.7 mmol; CASRN 474554-50-2), 37 (0.28 g, 1.8 mmol), Pd(PPh3)3 (0.19 g, 0.17 mmol) and Na2CO3 (0.53 g, 5.0 mmol) in DCM/MeOH (3:1, 8 mL) was subjected to microwave heating to 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.44 g (82%) of 3-(3-tert-butyl-4-methoxy-5-nitrophenyl)-2-methoxypyridine (98) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Cl-].[NH4+:11].[C-:12]#[N:13].[Na+]>[OH-].[NH4+].O>[NH2:11][C:6]1([C:12]#[N:13])[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: CON1CCC(=O)CC1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
To 10 g of N-methoxy-4-piperidone (Journal of Organic Chemistry (1961), 26, 1867-74) in 240 ml of ammonium hydroxide (25% in water) was added 6.2 g of ammonium chloride and 4.6 g of sodium cyanide. After stirring for 18 hours at 25° C. the reaction mixture was diluted with 200 ml of water and extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate and evaporated. 8.25 g of 4-amino-1-methoxy-piperidine-4-carbonitrile was obtained as a light brown oil, which was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[CH:28]>>[CH3:18][C:13]1([CH3:17])[S:14][CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:28][C:27]#[CH:26])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@H:12]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Yield: 95 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.30 g (0.775 mmoL) of tert-butyl(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.054 mL (0.93 mmol) of propargyl alcohol gave 0.313 g of tert-butyl(3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxylate as a white solid. Electrospray Mass Spec 426.4 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:37].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH2:37])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCN)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (5.0 g) is reacted with ammonia following the procedure outlined in example 39 and reduced with lithium aluminium hydride (3.0 g) in THF at room temperature. Aqueous work-up and crystallisation from methanol gives 2.6 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-amino-5α-chola-8,14-diene.
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].[K+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH:7]=1>CN(C)C=O.O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])[CH:7]=1
Reactant: [C-]#N
Reactant: ClCCCCCCc1cccnc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCCCc1cccnc1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A mixture of 4.0 g of potassium cyanide, 0.85 g of potassium iodide and 10.1 g of 6-(3-pyridyl)hexyl chloride in 100 ml of dimethylformamide was heated at 100° C. overnight. The reaction mixture was diluted with 200 ml of water and was extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and were evaporated. The residue was distilled to give 8.1 g (84%) of 3-pyridine heptanenitrile.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=CC1CCSCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCSCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
In 150 ml of ethanol is dissolved 10 g of ethyl 3-(4-thianyl)acrylate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 9 g of 10% palladium-carbon (50% in water) as a catalyst. The reaction mixtuure is stirred at room temperature for 20 minutes and at 50° C. for 8 hours, and the catalyst is removed by filtration. Nine (9) g of 10% palladium-carbon (50% in water) is added anew to the filtrate, followed by stirring at 50° C. for one day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give 9.1 g of ethyl 3-(4-thianyl)propionate as an oily material.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[N:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[S:36][C:37]=1[CH3:38]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[S:36][C:37]([CH3:38])=[C:33]([CH3:32])[N:34]=3)(=[O:40])=[O:41])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nc(S(N)(=O)=O)sc1C
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)sc1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4,5-dimethyl-1,3-thiazole-2-sulfonamide: 1H-NMR (CDCl3) δ 7.45-7.24 (9H, m), 6.47 (1H, br.s), 3.50-3.42 (2H, m), 2.88-2.82 (2H, m), 2.41 (3H, s), 2.35 (3H, s), 2.31 (3H, s), 2.24 (3H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][CH:29]1[CH2:46][C:32]2[C:33]3[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=3[CH:39]=[C:40]([N+:41]([O-:43])=[O:42])[C:31]=2[CH2:30]1>O1CCCC1.CN(C)C=O>[N+:41]([C:40]1[C:31]2[CH2:30][CH:29]([NH:28][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:46][C:32]=2[C:33]2[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=1)([O-:43])=[O:42]
Reactant: O=C(O)c1cccs1
Reactant: NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1cccs1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of thiophene-2-carboxylic acid (1 mmol) in anhydrous tetrahydrofuran (THF) was treated with carbonyldiimidazole (1.2 mmol) and triethyl amine (1 mL) and heated at 60° C. for 30 min. After cooling to room temperature a solution of 8-amino-6-nitro-4,7,8,9,-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (1 mmol) in dimethylformamide (DMF) was added. The reaction mixture as stirred at room temperature for 2 h, then heated at 70° C. for 2 h. The solvent was evaporated and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C16H12N4O5S.H2O: C, 49.22; H, 3.61; N, 14.35, found: C, 49.06; H, 312; N, 15.05. MS M+1 (373).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8]I.[O:10]=[C:11]1[CH:15]([S:16][C:17]2[C@H:18]([CH3:31])[C@@H:19]3[C@@H:26]([C@H:27]([OH:29])[CH3:28])[C:25](=[O:30])[N:20]3[C:21]=2[C:22]([O-:24])=[O:23])[CH2:14][CH2:13][NH:12]1.[Na+].CN(C)C=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:10]=[C:11]1[CH:15]([S:16][C:17]2[C@H:18]([CH3:31])[C@@H:19]3[C@@H:26]([C@H:27]([OH:29])[CH3:28])[C:25](=[O:30])[N:20]3[C:21]=2[C:22]([O:24][CH2:8][C:3]2[O:4][C:5](=[O:7])[O:6][C:2]=2[CH3:1])=[O:23])[CH2:14][CH2:13][NH:12]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CCNC3=O)[C@H](C)[C@H]12
Reactant: Cc1oc(=O)oc1CI
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(=O)oc1COC(=O)C1=C(SC2CCNC2=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 45.7 %

Procedure:
A solution of 66 mg of 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl iodide (prepared by heating 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide and sodium iodide under reflux in acetone) in chloroform was added to a mixture of 47.6 mg of sodium (1R, 5S, 6S)-2-(2-oxo-3-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.4 ml of dry dimethylformamide. The mixture was stirred at room temperature for 80 minutes and then at 30°-45° C. for 4.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed four times with an aqueous solution of sodium chloride. The extract was dried and the solvent was distilled off under reduced pressure. The residue was purified by Lobar column chromatography (Merck, LiChroprep Si60, size A), eluted with a 10:1 by volume mixture of ethyl acetate and methanol, to give 27.4 mg of the title compound in the form of a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[ClH:1].[CH3:22][N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N2CCc3ccccc3C2)c2ccccc2n1
Product: Cl
Yield: 42 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 0.9 g of the compound(3 mM) prepared in Example 1 and 15 ml of dimethylformamide, 0.4 ml of N-methylaniline(3.6 mM) was added, 0.51 g of the title compound was prepared.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
Methyl 3-(4-(2-quinolinylmethyloxy)benzyl)benzoate (0.05 mol) is heated at reflux in a 9:1 mixture of ethanol and 0.5 N aqueous NaOH (450 ml). After several hours the clear reaction is evaporated. The solid residue is takenup in water and acidified. The resulting crystalline product is isolated byfiltration and dried by suction with a rubber dam to obtain 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])N=N[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH:28](N1CCCC1)=[CH2:29]>C(Cl)(Cl)Cl>[C:15]1([C:14]2[CH:28]=[CH:29][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following General Procedure D, ethyl 5-(4-trifluoromethylphenyl)-6-phenyl-1,2,4-triazine-3-carboxylate (Compound 19, 1 g, 2.68 mmol) and crude 1-vinylpyrrolidine (Compound 38, 1.4 g) in CHCl3 (20 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36].C(N(CC)CC)C>ClCCl>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]([N:34]([CH3:38])[CH3:33])=[O:36])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 47.6 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in dichloromethane (1 mL) was added N,N-dimethylcarbamoyl chloride (18 μL, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at 40° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 40 mg (46%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, 1 H), 7.87-7.97 (m, 1 H), 7.79 (dd, 1 H), 7.59 (d, 1 H), 7.28-7.39 (m, 5 H), 7.14 (dd, 1 H), 6.58-6.65 (m, 1 H), 5.65 (d, 2 H), 3.63 (s, 2 H), 3.32-3.40 (m, 1 H), 2.85 (s, 2 H), 2.74 (d, 6 H), 1.99 (s, 2 H), 1.66 (s, 2 H); ES-MS m/z 495.20 [M+H]+, HPLC RT (min) 2.69.
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:61]=[CH:60][C:38]2[N:39]([C:47]([C:49]3[CH:50]=[CH:51][C:52]4[O:57][CH2:56][C:55](=[O:58])[NH:54][C:53]=4[CH:59]=3)=[O:48])[C@@H:40]([CH2:43][C:44]([OH:46])=O)[CH2:41][O:42][C:37]=2[CH:36]=1.[NH4+].[Cl-].CCOC(C)=O>C(Cl)Cl>[Cl:34][C:35]1[CH:61]=[CH:60][C:38]2[N:39]([C:47]([C:49]3[CH:50]=[CH:51][C:52]4[O:57][CH2:56][C:55](=[O:58])[NH:54][C:53]=4[CH:59]=3)=[O:48])[C@@H:40]([CH2:43][C:44]([NH2:4])=[O:46])[CH2:41][O:42][C:37]=2[CH:36]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
PyBOP (127 mg, 0.24 mmol) and TEA (0.141 mL, 1.02 mmol) was added to a solution of {(3S)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 22a, 82 mg, 0.20 mmol) in DCM (2 mL). Thereafter, NH4Cl (43.6 mg, 0.81 mmol) was added and the mixture was stirred at rt for 1.5 h. EtOAc (30 mL) was added and the mixture was washed with sat. aq. Na2CO3 (30 mL), HCl (0.5M, 20 mL) and brine (20 mL). The product was purified by preparative HPLC (Phenomenex Luna Hilic column (5 μm 250×30 ID mm) using a gradient of 10 to 45% MeOH/DEA 100/0.5 in CO2, 120 bar, over 6 min at 40 OC) to give the title compound (42.0 mg, 51.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([C@@H:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:12])[N:10]=2)[CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.[F-].[Cs+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[C:9]([C@@H:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:12])[N:10]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1I
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1-c1cccnc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-benzyl (1-(6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-yl)ethyl)carbamate (100 mg, 0.22 mmol) and pyridine 3-yl-boronic acid (30.7 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added cesium fluoride (66.8 mg, 0.440 mmol) at 25° C. The reaction mixture was degassed with nitrogen for 30 min and then tetrakis triphenylphosphine palladium(0) (13 mg, 0.011 mmol) was added at 25° C. The reaction mixture was stirred overnight at 100° C. After completion of the reaction water was added and the mixture extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide (S)-Benzyl (1-(6-fluoro-3-(pyridine-3-yl)imidazo[1,2-a]pyridine-2-yl)ethyl)carbamate: LC-MS (ESI)] m/z 391.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](N)[CH:36]=1)=[O:34]>CN(C=O)C>[C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:32].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: CC(=O)c1cccc(N)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1.0 gram (g), 4.1 millimoles (mmol) is solubilized in 45 milliliters (ml) of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 microliters (μl), 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 minutes (min), and then 3-aminoacetophenone (824 mg, 6.10 mmol) and N-methylmorpholine (480 μl, 4.35 mmol) in 10 ml of DMF are added. The solution is maintained stirred at 0° C. for 2 hours (h), and then evaporated to dryness. The residue is taken up in 3 ml of MeOH, and then 50 ml of water are added. The precipitate obtained is filtered, washed with water, CH2Cl2 and ether to give 1.2 g (80%) of crude product 1a. Recrystallization from the MeOH—H2O pair gives 1a (1.01 g, 70%) in the form of a white powder.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)=[C:8]([F:28])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:30]1[C:31]2[N:38]=[CH:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:32]=2[N:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:30]3[C:31]4[N:38]=[CH:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:32]=4[N:33]=[N:34][CH:35]=3)[CH:13]=2)=[C:8]([F:28])[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)c(F)c1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)c(F)c1
Temperature: 120 °C
Yield: 80 %

Procedure:
To a solution of 2-[4′-(ethylsulfonyl)-2′,6-difluorobiphenyl-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 47, 48 mg, 0.12 mmol) and 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 22 mg, 0.11 mmol) in anhydrous dioxane (0.56 mL) was added aqueous Na2CO3 solution (2M, 0.17 mL, 0.34 mmol) and a stream of nitrogen gas was bubbled through the suspension for 5 minutes. Tetrakistriphenylphosphine palladium(0) (2.3 mg, 0.002 mmol) was added and the mixture was heated under microwave irradiation at 120° C. for a total of 15 minutes. The reaction mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo to leave a tan sticky solid that was purified by silica gel column chromatography eluting with heptane:EtOAc to afford the title compound as a tan solid in 80% yield, 40 mg.