Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:6]1[C:7]([Cl:13])=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:12][C:9]1[N:8]=[C:7]([Cl:13])[C:6]([CH:2]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:3]([CH3:5])[CH3:4])=[CH:11][N:10]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)C(Br)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(NC(c2cnc(Cl)nc2Cl)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-5-(1-Bromo-2-methyl-propyl)-2,4-dichloro-pyrimidine (88.7 mg; 0.312 mmol) (from Example 11b supra) was combined with potassium carbonate (47.4 mg; 0.34 mmol), potassium iodide (14.9 mg; 0.09 mmol) and p-anisidine (38.7 mg; 0.31 mmol) (Aldrich) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and then brine. The organic phase with dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage 12M; 10:90 to 30:70 ethyl acetate-hexanes gradient) gave (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-2-methyl-propyl]-(4-methoxy-phenyl)-amine. (Yield 17.6 mg; 17.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([OH:10])=[N:8][S:7][N:6]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([O:10][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:8][S:7][N:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3O)c(Cl)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nsnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
200 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole and 150 mg of methyl bromoacetate were dissolved in 10 ml of N,N-dimethylformamide, to this was added 100 mg of potassium carbonate, and the mixture was stirred for 3 hours at room temperature. This reaction solution was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was washed with hexane to obtain 0.18 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-1,2,5-thiadiazole [present compound 10-7].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:11]3=[N:10][N:9]=2)=[CH:4][CH:3]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C:11]3=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nnc3cnccn23)cc1
Agent: [Pd]
Solvent: CCO
Product: Clc1ccc(-c2nnc3n2CCNC3)cc1
Yield: 86 %

Procedure:
3-(4-Chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (2.01 g) was hydrogenated under atmospheric hydrogen with 10% Pd/C (400 mg Celite® (diatomaceous earth)) as a catalyst in ethanol (20 mL) at RT for 18 h. The reaction mixture was filtered through and concentrated. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) afforded 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (86% yield) as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccccc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccccc3n2CCc2ccccc2)C1

Procedure:
The title compound was prepared according to General Method 2. 2,3,4,5-Tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 1.07), styrene (1.23 mL mmol, 10.65) and NaH (250 mg, 6.25 mmol) in DMF (6 ml) at 200° C. for 16 h to obtain 15 mg of 2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [I-:1].Br[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][N+:6]([CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([I:28])C>>[I-:28].[CH2:19]([N+:6]1[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:3]([I:1])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1)[CH3:26]
Reactant: C[n+]1cc(-c2ccccc2)c(Br)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CCI
Agent: [I-]
Product: CC[n+]1cc(-c2ccccc2)c(I)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 72 h

Procedure:
A 2 g. portion of the 4-bromopyridine intermediate of Example 9 was combined with 10 ml. of ethyl iodide and allowed to stand at room temperature for 3 days. Volatile materials were then evaporated under vacuum, and the solids were crystallized from chloroform-hexane, yield 0.25 g., m.p. 235°-238°. Analysis by nuclear magnetic resonance and mass spectrometry techniques identified the product as consisting of approximately 60 percent of the compound of Example 12, and approximately 40 percent of the compound of Example 13.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:25])=[O:9])=[O:4]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (1.37 g, 4.69 mmol, 1.00 equiv) in dichloromethane (17 mL) was added 2 drops of N,N-dimethylformamide followed by the addition of oxalyl dichloride (3.63 g, 28.14 mmol, 6.00 equiv). The resulting solution was stirred for 1 h at 50° C. in an oil bath then concentrated under vacuum to afford 1.41 g (87%) of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride as a gray-yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[C:14]([CH:16]=1)[NH2:15].CCCCCC>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[C:14]([NH:15][C:1](=[O:3])[CH3:2])[CH:16]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)cc(C(F)(F)F)c1
Reaction time: 1.5 h

Procedure:
Acetic anhydride (1.22 ml, 12.8 mmol) is added during 10 min to a solution of 5-methoxy-3-trifluoromethyl-aniline (2.29 g, 12.0 mmol) in toluene (10 ml) at a temperature of 25-33° C. After 90 min at RT, hexane (10 ml) is added und the suspension is stirred for 20 min. Filtration, washing with toluene/hexane 2:1 and hexane gives the title compound: mp: 123-124° C.; API-MS: 234 [MH]+; TLC: Rf=0.27 (Hex/EtOAc, 1:1).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][CH2:26][CH2:27][CH:28]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:13][O:12][C:7]1[C:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][CH2:28][CH2:27][CH2:26][CH2:25][N:16]3[C:17](=[O:24])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]3=[O:14])[C:11]=2[N:10]=[CH:9][CH:8]=1
Reactant: COc1ccnc2c1CCCC2N
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc2c1CCCC2NCCCCN1C(=O)c2ccccc2C1=O
Yield: 54.4 %

Procedure:
Using General Procedure B: Reaction of 8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline (0.297 g, 1.67 mmol) and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (0.371, 1.71 mmol) with NaBH(OAc)3 (0.493 g, 2.33 mmol) in CH2Cl2 (8 mL) for 60 minutes followed by purification of the crude material by column chromatography on silica gel (20:1 CH2Cl—2—CH3OH) provided 0.345 g (54%) of 2-[4-(4-Methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1O
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 92 %

Procedure:
Analogously to example 1 (f), the reaction of 684 mg of 4-[5-(4-chlorobenzyl)-7-isobutyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenol with tert-butyl bromoacetate gave 800 mg (92%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=[O:10])[C:3]=1[NH:12][C:13](=[O:18])[CH2:14]C(=O)C.[OH-].[Na+].Cl>C(O)(C)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[N:12]=[C:13]([OH:18])[CH:14]=[N+:9]2[O-:10]
Reactant: CC(=O)CC(=O)Nc1c(Br)cc(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Br)c2nc(O)c[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
The title compound of Step B (11.75 g, 37.29 mmol) was suspended in a mixture of isopropanol (120 mL) and water (120 mL) at room temperature under a nitrogen atmosphere. A solution of sodium hydroxide (14.91 g of a 50% aqueous solution, 186.4 mmol) diluted with water (10 mL) was added dropwise to the mixture over 30 min. The mixture was allowed to stir at room temperature overnight. First, 1N hydrochloric acid and then concentrated hydrochloric acid were added dropwise to the reaction mixture until the pH was approximately 2. Solids were filtered from the reaction mixture. These solids were washed with water and then cold ethyl acetate to afford the title compound of Step C as a reddish-brown solid melting at 241°-243° C. (8.67 g, 91%). 1H NMR ((CD3)2SO): δ2.47 (s,3H), 7.69 (s, 1H), 7.81 (s, 1H), 8.12 (s, 1H), 8.9 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][C@@H:7]1[CH2:20][C@@H:19]2[C@H:10]([C@H:11]3[C@H:16]([CH2:17][CH2:18]2)[CH2:15][C@:14]2([CH3:25])[C:21](=O)[CH2:22][CH2:23][C@H:13]2[CH2:12]3)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].Cl.[NH2:29][OH:30].O>N1C=CC=CC=1>[CH3:1][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][C@@H:7]1[CH2:20][C@@H:19]2[C@H:10]([C@H:11]3[C@H:16]([CH2:17][CH2:18]2)[CH2:15][C@:14]2([CH3:25])[C:21](=[N:29][OH:30])[CH2:22][CH2:23][C@H:13]2[CH2:12]3)[CH2:9][CH2:8]1)([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@]4(C)C(=O)CC[C@H]4C[C@H]32)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@]4(C)C(=NO)CC[C@H]4C[C@H]32)C1
Reaction time: 14 h
Yield: 78.4 %

Procedure:
To a solution of compound 4 (130 mg, 0.33 mmol) in pyridine (10 mL) was added hydroxylamine hydrochloride (140 mg, 2.0 mmol) at room temperature. After 14 h, water was added and the product extracted into EtOAc (50 mL×2). The combined extracts were dried, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to afford compound 5 (105 mg, 82%): 1H NMR (CDCl3) δ 9.00 (s, br, 1H), 3.95-4.00 (m, 1H), 2.45-2.51 (m, 2H), 0.87 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3) δ 171.0, 66.7, 48.5, 48.1, 47.4, 44.0, 41.9, 41.4, 38.2, 36.2, 34.1, 33.7, 27.9, 25.8, 25.4, 25.0, 23.4, 18.1, 17.0, −4.96, −4.91.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[F:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](I)[CH:17]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[N:14][CH:13]=1
Reactant: Fc1cncc(I)c1
Reactant: C#Cc1nc(C)ccc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cncc(F)c2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22 %

Procedure:
To a solution of Cul (11 mg, 0.06 mmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (40 mg, 0.30 mmol, described in Example 7), (PPh3)2PdCl2 (21 mg, 0.06 mmol), and 3-fluoro-5-iodopyridine (111 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 14 h. The solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 7:3) to yield 15 mg (66 μmol, 22%) of (2-(5-fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:48][C:49]1[C:57](O)=[CH:56][CH:55]=[C:54]2[C:50]=1[CH:51]=[N:52][NH:53]2.Cl.O1CCOCC1>O1CCCC1.CO>[ClH:48].[NH:24]1[CH2:23][CH2:22][CH:21]([O:20][C:57]2[C:49]([Cl:48])=[C:50]3[C:54](=[CH:55][CH:56]=2)[NH:53][N:52]=[CH:51]3)[CH2:26][CH2:25]1
Reactant: Oc1ccc2[nH]ncc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Clc1c(OC2CCNCC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.3 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (179 mg, 0.890 mmol) and diisopropyl azodicarboxylate (193 μl, 0.979 mmol) were added at 0° C. to a solution of the 4-chloro-1H-indazol-5-ol (150 mg, 0.890 mmol) obtained in Example 468 in tetrahydrofuran (6 ml). After 30 minutes, the mixture thus obtained was heated to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and then washed with a 1M-aqueous sodium hydroxide solution. After the aqueous layer was re-extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The oil thus obtained was dissolved in methanol (3 ml) at room temperature and 4N-hydrochloric acid-dioxane (3 ml) was added thereto. After 1 hour, the mixture thus obtained was concentrated under reduced pressure and the resulting residue was washed with ethyl acetate by repulping to obtain 5-(piperidin-4-yloxy)-4-chloro-1H-indazole hydrochloride (219.7 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[F-].[Cs+].I[CH:36]([CH3:38])[CH3:37]>C(#N)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH:36]([CH3:38])[CH3:37])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]=2[C:22]([F:24])([F:25])[F:23])[O:11][N:10]=1
Reactant: CC(C)I
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)OC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Yield: 79.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.064 mmol), cesium fluoride (12 mg, 0.077 mmol) and 2-iodopropane (0.008 mL, 0.077 mmol) were dissolved in dried acetonitrile (1 mL) and the mixture was refluxed for 20 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was solvent removed under reduced pressure. The product was purified by pTLC (PE/EE 9/1) to give 26 mg of a yellow oil (yield 79 To). Result of LC/MS [M+H]+: 511.8; 1H NMR (CDCl3): 1.02 (6H, d, 2×CH3), 5.02 (1H, m, CH-propyl), 7.18 (1H, t, CH-arom.), 7.28-7.61 (6H m, CH-arom.), 8.31 (1H, s, CH-pyraz.).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[CH2:30][Mg:31][Br:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:37]1([C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[CH2:45]Br)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:22]1([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[CH2:30][Mg:31][Br:32])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[C:43]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH2:45][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[OH:15]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: O=C(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Agent: Br[Mg]Cc1ccccc1-c1ccccc1
Product: OC(Cc1ccccc1-c1ccccc1)(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Reaction time: 8 h

Procedure:
Compound 55 is prepared from 8 (0.56 g, 1.94 mmol) and 2-phenyl benzyl magnesium bromide solution (0.25 M solution in diethyl ether, 9.31 mL, 2,33 mmol, 1.2 eq) following General Procedure 2. 2-Phenylbenzyl magnesium bromide is prepared from commercially available (Aldrich) 2-phenylbenzyl bromide following General Procedure 5. Further 2-phenyl benzyl magnesium bromide solution (1 mL) is added and the reaction left under stirring overnight. Purification by ion exchange chromatography gives 55 as an off-white foam-like solid (0.37 g, 68%). MW 457.62; C30H35NO3; LCMS. (6 minute method): m/z 458 [M+H]+, RT 3.58 min.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([CH3:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([CH3:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1CNC(=O)OC(C)(C)C
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1CN

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-[(2R/S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C23H26ClN5O2 (439.94); mass spectrum: (M+H)+=440/442 (chlorine isotope).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.P(Cl)(Cl)(Cl)=O.O.CN([CH:19]=[O:20])C>>[N:1]1[CH:2]=[C:3]([CH:19]=[O:20])[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Imidazo[1,2-a]-pyrazine (0.30 g, 2.5 mmol) was dissolved in anhydrous DMF (10.0 mL) and added to a preformed solution of phosphorous oxychloride (0.26 mL, 2.8 mmol) in anhydrous DMF (10.0 mL). The solution was allowed to stir 72 h under nitrogen at RT. The solution was then poured into water (100 mL) and residual organics extracted with diethyl ether (3×30 mL). The remaining aqueous portion was concentrated to dryness under a nitrogen stream to yield the title compound (0.050 g). MS (ESI+) for m/z 148 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[S:8][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1 g) and sodium borohydride (0.12 g) in methanol (19 ml) was stirred at ambient temperature for 2 hours. Acetic acid (1 ml) was added and the mixture was concentrated. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was recrystallized from a mixture of hexane and ethyl acetate to give crystals of 2-(4-fluorophenyl)-5-(1-hydroxyethyl)-3-[4-(methylsulfonyl)phenyl]thiophene (0.74 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[CH2:18][N:19]=[C:20]=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH:13][C:20]([NH:19][CH2:18][C:17]3[CH:22]=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=3)=[O:21])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C=NCc1cccc(F)c1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(F)c1)NNC(=O)c1ccc2c(c1)CCO2
Yield: 64.8 %

Procedure:
A solution of 2,3-dihydro-1-benzofuran-5-carbohydrazide (0.50 g, 2.81 mmol) and 3-fluorobenzyl isocyanate (0.85 g, 5.61 mmol) in pyridine (5 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (0.60 g, yield 65%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1.CO[C:33](OC)([N:35]([CH3:37])[CH3:36])[CH3:34]>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][N:4]1[C:5](=[O:21])[C:6]2[C:10]([O:11][CH3:12])=[C:9]3[C:13](=[O:20])[N:14]([CH2:18][CH3:19])[CH2:15][C@H:16]([CH3:17])[N:8]3[C:7]=2[C:2]([N:1]=[C:33]([N:35]([CH3:37])[CH3:36])[CH3:34])=[N:3]1
Reactant: COC(C)(OC)N(C)C
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N=C(C)N(C)C)c32)C1=O

Procedure:
A solution of (6S)-4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.20 g, 0.46 mmol; Example 120, step 3) and N,N-dimethylacetamide dimethyl acetal (0.37 mL, 2.51 mmol) in anhydrous DMF (50 mL) was stirred in an oil bath at 40° C. overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound.