Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[N:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(C)cn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.11 g, 5.0 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.065 g, 0.55 mmol) was added and stirred for further 2 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.09 g, 54% yield). 8-Chloro-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.09 g, 0.26 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.034 g, 0.26 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.08 g, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.14 g, 0.46 mmol) with boron tribromide (0.69 mL of 1N solution, 0.69 mmol) according to method D to yield 0.050 g (38%) of a white solid mp 174-176° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.62 Hz), 7.33 (1H, d, J=8.92 Hz), 7.60-7.67 (3H, m), 7.86 (1H, dd, J=1.43 Hz, J=9.02 Hz), 7.95 (1H, d, J=1.37 Hz), 9.68 (1H, s), 10.59 (1H, s); MS (ESI) m/z 287/289 (M−H)−.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH3:2].[O:12]1CCOC[CH2:13]1>>[CH2:1]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:10])[NH:11][C:13]1=[O:12])[CH3:2]
Reactant: CCNc1c(N)ncnc1Cl
Reactant: C1COCCO1
Product: CCn1c(=O)[nH]c2ncnc(Cl)c21
Yield: 60 %

Procedure:
A solution of N5-ethyl-6-chloropyrimidine-4,5-diamine (0.21 g, 1.22 mmol) and 1,1-carbonyldiimidazole (0.40 g, 2.44 mmol) in 1,4-dioxane (5 mL) was degassed, flushed with nitrogen and refluxed under nitrogen for 22 h. The solution was cooled and partitioned between ethyl acetate (15 mL), 1M hydrochloric acid (10 mL) and brine (5 mL). The organic layer was dried, filtered and concentrated to give 7-ethyl-6-chloro-7,9-dihydropurin-8-one (0.146 g, 0.735 mmol, 60%) as a yellow solid. LC-MS (LCT2) m/z 199, 201 [M+H+], Rt 4.62 min.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[C:12]([CH:14]=[C:15]3[CH2:20][C@@H:19](O)[CH2:18][CH2:17][C@:16]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2)=[O:13].[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>N1C=CC=CC=1>[C:26]([C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][C:12](=[O:13])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:20]1)([O:25][CH2:23][CH3:24])=[O:27]
Reactant: CCOC(=O)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 90 %

Procedure:
Prepared from (2) and ethylchloroformate in pyridine at 0-5° C. Yield 90%, m.p. 187-8° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2>[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:8]1([CH3:18])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:20][CH3:21])[CH:11]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)[C:10]([OH:17])([C:13]([F:16])([F:14])[F:15])[CH2:9]1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 2.7 %

Procedure:
Analogously to Example 3, the corresponding imine is produced starting from 500 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 260 mg of 5-aminoquinolin-2(1H)-one. By reaction of 80 mg of the imine with 0.5 ml of titanium tetrachloride (1 M in dichloromethane), 20 mg of the title compound is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]12[CH2:9][C:7]([CH3:10])([CH2:8]1)[CH2:6][N:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:4]2.[P:16](=[O:20])([OH:19])([OH:18])O.ClC1C=CC=CC=1.P(Cl)(Cl)Cl>O.CO>[CH3:2][C:3]12[CH2:9][C:7]([CH3:10])([CH2:8]1)[CH2:6][N:5]([CH2:11][CH2:12][C:13]([OH:15])([P:16]([OH:20])(=[O:18])[OH:19])[P:16]([OH:19])(=[O:20])[OH:18])[CH2:4]2
Reactant: O=P(O)(O)O
Reactant: CC12CN(CCC(=O)O)CC(C)(C1)C2
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: CO
Solvent: O
Product: CC12CN(CCC(O)(P(=O)(O)O)P(=O)(O)O)CC(C)(C1)C2

Procedure:
11.68 g (0.05 mol) of 3-(1,5-dimethyl-3-aza-bicyclo[3,1,1]hept-3-yl)-propionic acid hydrochloride, 6.6 ml of 84% phosphoric acid and 23 ml of chlorobenzene are heated to 105° with stirring. 13.5 ml of phosphorus trichloride are slowly added dropwise and the reaction mixture is subsequently maintained at 105° for a further 3 hours. The chlorobenzene is then distilled off under reduced pressure, leaving a viscous mass. 50 ml of water are added to the latter and the mixture is boiled under reflux for 1 hour with stirring. The mixture is then completely concentrated by evaporation under reduced pressure. Upon stirring the residue with acetone and decanting, a colourless oil is obtained which is then dissolved in 50 ml of hot water. Upon adding 140 ml of hot methanol and cooling, colourless crystals of 3-(1,5-dimethyl-3-aza-bicyclo[3,1,1]hept-3-yl)-1-hydroxy-propane-1,1-diphosphonic acid are obtained; m.p. 245°-247° (decomposition); formula ##STR14## The 3-(1,5-dimethyl-3-aza-bicyclo[3,1,1]hept-3-yl)-propionic acid hydrochloride used as starting material can be prepared in the following manner:
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[S:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(5-(4-(4-tert-butylbenzamido)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (110 mg) in THF (2.2 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.44 ml) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, concentrated under vacuum to get off white solid which was crystallized in EtOAc to give the title compound. Yield: 87 mg (81%); 1H NMR (DMSO-d6, 300 MHz): δ 13.02 (bs, 1H), 10.38 (s, 1H), 8.4 (s, 1H), 8.36 (d, 1H), 7.94 (d, 2H), 7.91 (d, 2H), 7.8 (d, 2H), 7.58 (d, 2H), 4.32 (m, 1H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 480 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C.O>CN(C)C=O>[N:52]1([CH:56]2[CH2:61][CH2:60][N:59]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]5([C:40]([NH:41][C:42]6[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=6)=[O:49])[CH2:39][CH2:38]5)=[O:36])=[C:2]([F:1])[CH:3]=4)[CH:11]=[CH:10][N:9]=3)=[O:14])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-yl)piperidine dihydrochloride (79.9 mg), triethylamine (0.105 ml) and water (0.050 ml), followed by stirring at room temperature for 24 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (22.9 mg, 51.7%).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cnn2c(-c3ccccc3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1cnn2c1NCC=C2c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 6.0 g amount of 7-phenylpyrazolo[1,5-a]-pyrimidine-3-carboxamide (prepared as described in Example 2) was stirred under nitrogen as a suspension in 120 ml of glacial acetic acid (cooled in an ice bath) and then 3.5 g of sodium cyanoborohydride was added to the reaction mixture in portions. After one hour of stirring in the ice bath, the mixture was stirred at room temperature for 3.5 hours at which time the original solid dissolved. Stirring was continued for one hour longer then the solution was concentrated in vacuo. Water was added to the residue and a precipitate formed. The precipitate was collected by filtration and then was dissolved in dichloromethane. The organic solution was washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a solid. The solid was recrystallized from isopropyl alcohol to give 5.0 g of the desired product as a white solid, m.p. 149°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[S:37]([NH:40][CH2:41][CH3:42])(=[O:39])=[O:38]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:37]([NH:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C20H15F4N5O2S, 465.09; m/z found, 465.8 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 2H), 8.11-8.07 (m, 1H), 7.87-7.81 (m, 1H), 7.72 (d, J=7.9, 1H), 7.69-7.63 (m, 1H), 7.45 (dd, J=10.8, 1.7, 1H), 7.43-7.36 (m, 3H), 2.78 (qd, J=7.2, 5.5, 2H), 0.97 (t, J=7.2, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)=O)(C)(C)C>>[N:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH2:24][C:23](=[O:39])[NH:16][C:9]3[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:28][C:29]=1[C:33]1[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2ccncc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1ccnc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (90 mg, 0.35 mmol) and 3-[2,4′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K58) (104 mg, 0.35 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (120 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([C:45]([O-])=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[Li+]>>[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([CH2:45][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 75 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (100 mg) according to an analogous synthetic method to Example 152, the title compound (40 mg) was obtained.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[OH:13][C:14]([CH3:18])([CH3:17])[C:15]#[N:16].O>C(Cl)Cl>[N:3]1([C:1]([O:13][C:14]([C:15]#[N:16])([CH3:18])[CH3:17])=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(C)(O)C#N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)OC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A mixture of 1,1′-carbonyldiimidazole (5 g, 31 mmol) and 2-hydroxy-2-methylpropanenitrile (2.6 g, 31 mmol) in DCM was stirred at rt overnight. Water was added and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with ethyl acetate, to give 2.7 g (50%) of the title compound.
Reaction SMILES: [N:1]([CH:4]([CH3:26])[CH:5]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:6][C:7]1[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>O1CCCC1.O>[NH2:1][CH:4]([CH3:26])[CH:5]([C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[CH2:6][C:7]1[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N=[N+]=[N-])o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N)o1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
3.24 g of ethyl 5-{(2RS,3RS)-3-azido-2-(4-nitrophenyl)butyl}-2-furancarboxylate was dissolved in a mixed solution of 50 ml of tetrahydrofuran and 5 ml of water, and 2.37 g of triphenylphosphine was added thereto, followed by heating and refluxing or 6 hours. The reaction solution was left to cool to room temperature, and then ethyl ether and water were added thereto for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1→20/1) to obtain 2.89 g of the above-identified compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[C:11](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:12]>ClCCl>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1)=[C:11]=[S:12]
Reactant: Cc1nc(N)ccc1C#N
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1nc(N=C=S)ccc1C#N
Temperature: 40 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To 6-amino-2-methylnicotinonitrile (0.41 g, 3.08 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.75 g, 3.23 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature. The crude was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 6-isothiocyanato-2-methylnicotinonitrile (0.52 g, 2.97 mmol, 96% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.36 (d, J=8.24 Hz, 1H), 7.39 (d, J=8.24 Hz, 1H), 2.65 (s, 3H). MS (LC/MS) R.T.=2.09; [M+H]+=176.0.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[N:24]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:32][CH2:31][CH2:30][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OCCN1CCCCC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(OCCN2CCCCC2)c2cc(C3OCCO3)ccc21

Procedure:
The title compound was prepared from 600 mg (1.344 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) in analogy to the procedure described in Example 21A. The procedure was modified by using 5 equivalents of 2-(piperidin-1-yl)ethanol as the alcohol reactant and by switching to toluene as solvent. Instead of using microwave irradiation, the reaction mixture was refluxed for 5 days employing conventional heating. During this time, the same amounts of catalyst and ligand were added again on day 3. The crude product thus obtained was purified by chromatography on silica gel (cyclohexane/ethyl acetate gradient) to afford 244 mg (32% of th.) of the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH:16]([CH2:21][CH3:22])[CH:17]([CH3:20])[CH2:18][CH3:19])[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>CO>[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:15][CH:16]([CH2:21][CH3:22])[CH:17]([CH3:20])[CH2:18][CH3:19])=[CH:32][CH:31]=1
Reactant: CCC(C)C(CC)SC(C#C[Si](C)(C)C)=Nc1ccccc1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(C)C(CC)SC(C=CSc1ccc(F)cc1)=Nc1ccccc1
Reaction time: 0.5 h

Procedure:
1-ethyl-2-methylbutyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.47 g) was dissolved to methanol (10 mL), small amount of potassium carbonate was added to the solution under ice-cooling and then it was stirred for 30 minutes. Then methanol (3 mL) of 4-fluorothiophenol (0.105 mL) was added to the solution and the mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was subjected to medium pressure HPLC (hexane/ethyl acetate=98/2) to obtain 1-ethyl-2-methylbutyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.09 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:14](=[O:15])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[Cl:18])=[CH:63][N:64]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(C(=O)NCCN4CCCC4)nc3)nc2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Intermediate 1 (Example 2) (0.076 g, 0.222 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.047 g, 0.266 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.05 mL, 0.443 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 23 (Example 31) (0.076 g, 0.233 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.081 g, 56%).
Reaction SMILES: [CH:1]1([C:4]2(N3CCCC3)[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.C(O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2=NOC(C3CC3)(N3CCCC3)C2)ccn1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1cc(-c2cc(C3CC3)on2)ccn1

Procedure:
To a solution of 2.6 g. of 4-[5-cyclopropyl-5-(1-pyrrolidinyl)-2-isoxazolin-3-yl]pyridine in 25 ml. of ethanol is added 1.4 g. of 70% perchloric acid dissolved in 5 ml. of ethanol. This solution is diluted wth 25 ml. of water and heated on a steam bath for 1.0 hour. The solution is poured onto cracked ice, made basic with 10 N sodium hydroxide and filtered to collect straw-colored crystals, melting point 76°-80°C., nmr spectrum δ6.84 (DMSO-d6, s, 4-isoxazolyl H).