Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=1>C(O)CCC>[NH:2]([C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=1)[NH2:3]
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1nc(NN)c2c(n1)NC(=O)CO2
Temperature: 25 °C
Yield: 56.3 %

Procedure:
12.8 ml of 98% hydrazine hydrate dissolved in 40 ml of n-butanol are dropped to a solution of 20 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one in 320 ml of n-butanol at 117° C. within 30 minutes while stirring. The mixture is stirred for an additional 45 minutes at 117° C., then cooled to room temperature. The precipitate is filtered and washed with water to give 11.66 g (56.3%) of the product, m.p.: 262°-264° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:19][NH2:20]>>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:19][N:20]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc([N+](=O)[O-])c(O)c2)=NN1

Procedure:
3-(3-Hydroxy-4-nitrobenzoyl)propionic acid was cyclised with an equimolar amount of hydrazine hydrate in a similar manner to that described in Example 3(i) to give 6-(3-hydroxy-4-nitrophenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[C:37]2[CH:38]=[CH:39][S:40][C:36]=2[C:35]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:44]4[CH2:45][CH2:46][N:41]([C:35]5[C:36]6[S:40][CH:39]=[CH:38][C:37]=6[N:32]=[CH:33][N:34]=5)[CH2:42][CH2:43]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1nc(N2CCNCC2)c2sccc2n1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ncnc3ccsc23)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-thieno[3,2-d]pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=648.99 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])=O.Cl.[NH2:18]O>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])#[N:18]
Reactant: NO
Reactant: COc1c(C=O)cc(C(=O)O)cc1C(C)C
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1C(C)C
Yield: 99.9 %

Procedure:
3-formyl-5-isopropyl-4-methoxybenzoic acid (15.85 g) was dissolved in formic acid (80 mL), and hydroxylamine hydrochloride (5.45 g) was added to the solution, and the mixture was refluxed for 19 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.62 g) as a brown solid.
Reaction SMILES: C([O:3][C:4]([C@:6]1([NH2:30])[C@H:11]([S:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)(=[O:14])=[O:13])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:29])[C:24]([O:26]CC)=[O:25])=[O:5])C.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:30][C@@:6]1([C:4]([OH:5])=[O:3])[C@H:11]([S:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)(=[O:14])=[O:13])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:29])[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1S(=O)(=O)Cc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1S(=O)(=O)Cc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
108 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester was stirred in 1.08 mL of 60% sulfuric acid (W/V %) for 3 days at 130° C. The reaction solution was ice-cooled and then neutralized in an aqueous solution of 5N sodium hydroxide. The mixture was stirred for 1 hour at room temperature and then purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 30% aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), thereby yielding 76 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]([CH3:25])=[N:18]1>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22]([C:21]2[N:17]([CH3:16])[N:18]=[C:19]([CH3:25])[CH:20]=2)=[O:23])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Yield: 89.6 %

Procedure:
In the same manner as in Reference Example 11 and using 3-aminophenol (2.11 g, 19.3 mmol), triethylamine (2.81 mL, 20.3 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.07 g, 19.4 mmol) and tetrahydrofuran (30 mL) as starting materials, the title compound (4.00 g, 90%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:35]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
Yield: 59.3 %

Procedure:
Starting with (5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (example 1-1, method A, 3rd step) (0.500 g, 1.8 mmol), diisopropylamine (0.553 g, 2.1 mmol) and 4-bromobenzenesulfonyl chloride (0.465 g, 1.8 mmol), using the method analogous to the one described for example 1-1, method A, 4th step, [5-(4-bromo-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (0.53 g, 61%) was obtained. MS cald. for C22H26BrNO5S 495, obsd. 496 [(M+H)+].
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([CH3:34])[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[C:16]=2[NH:21][C:22]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH3:26])=[O:23])=[CH:11][CH:10]=1)C.[OH-].[Li+]>CO.O>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:25]([O:24][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[N:18][O:19][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][CH2:6][C:5]([CH3:35])([CH3:34])[C:4]([OH:36])=[O:3])=[CH:14][CH:13]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(C)(C)CC#Cc1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(C#CCC(C)(C)C(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 5-(4-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-2,2-dimethyl-pent-4-ynoic acid ethyl ester (0.46 mmol) in MeOH and H2O was added lithium hydroxide, and the reaction was stirred at 60° C. overnight. The mixture was acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. Mass spec. data (M+H)=481.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([O:29][CH3:30])[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:23])[CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1.Cl[CH2:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[C:43]([F:53])[CH:42]=2)[CH2:37][CH2:36]1)=[O:34].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([O:29][CH3:30])[CH2:28][CH2:27][N:26]([CH2:32][C:33]([N:35]5[CH2:40][CH2:39][N:38]([C:41]6[CH:46]=[CH:45][C:44]([C:47]7[N:48]=[CH:49][CH:50]=[CH:51][N:52]=7)=[C:43]([F:53])[CH:42]=6)[CH2:37][CH2:36]5)=[O:34])[CH2:25]4)=[O:23])[CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Reactant: COCCOc1ccc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCNC4)cc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCN(CC(=O)N5CCN(c6ccc(-c7ncccn7)c(F)c6)CC5)C4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid {3-[4-(2-methoxy-ethoxy)-phenyl]-1H-indazol-5-yl}-amide (10AB) (50 mg, 0.103 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (42 mg, 0.124 mmol, 1.2 equiv) were weighed out in a flask and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (26.6 mg, 36 uL, 0.206 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][CH2:9][C@H:5]2[O:4][CH2:3]1>Cl.O1CCOCC1>[O:4]1[C@H:5]2[C@H:6]([NH:7][CH2:8][CH2:9]2)[C@@H:2]([OH:1])[CH2:3]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CC[C@H]2OC[C@H](O)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CO[C@@H]2CCN[C@H]12
Reaction time: 1 h

Procedure:
Preparation of (3R,3aR,6aR)-(9H-fluoren-9-yl)methyl 3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2b). Alcohol (2f) (558 mg, 2.43 mmol) was dissolved in 4M HCl in dioxane (14.06 mL) and left to stand at ambient temperature for 1 h. The solvent was removed in vacuo and the residue azeotroped from toluene (3×20 mL) to give hydrochloride salt of (3R,3aR,6aR)-hexahydro-2H-furo[3,2-b]pyrrol-3-ol (2g) used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:33]([F:36])([F:35])[F:34])=[CH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[N+:37]([CH3:40])([O-:39])=[O:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([CH2:40][N+:37]([O-:39])=[O:38])([C:33]([F:35])([F:34])[F:36])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Reactant: C[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a stirred solution of tert-butyl 5′-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 6, 6.54 g, 11.658 mmol) in DMF (215 mL) was added nitromethane (6.24 mL, 116.57 mmol) and DBU (1.69 mL, 11.3mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2×300 mL). Combined organic layer was washed with aqueous LiCl solution (2×400 mL) then brine (500 mL), dried over sodium sulfate and concentrated to get as semi solid (11.23 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to afford light yellow sticky liquid (4.51 g, 63.7%). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 9H), 1.85-1.88 (m, 1H), 2.16-2.17 (m, 1H), 3.40-3.44 (m, 1H), 3.95 (d, J=18.84 Hz, 1H), 4.13-4.18 (m, 2H), 4.33-4.36 (m, 2H), 5.17 (d, J=4.12 Hz, 2H), 7.13 (d, J=6 Hz, 1H), 7.26 (s, 1H), 7.63-7.65 (m, 1H), 7.76-7.78 (m, 1H), 8.00-8.02 (m, 1H). LC-MS (m/z): 605.0 (M−H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[C:22]([O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([C:29]1[CH:34]=[C:33]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][N:9]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([Cl:21])[CH:3]=2)[CH:32]=[CH:31][CH:30]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Yield: 80.1 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (500 mg, 1.35 mmol) and 3-(tert-butoxycarbonyl)phenylboronic acid (900 mg, 4.0 mmol) affords 506 mg (80%) of the title compound: Mass spectrum (apci) m/z=468.2 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(C)=O
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Compound 2 (4.10 g, 15.7 mmol) was suspended in a mixture of distilled pyridine (40 ml) and acetic anhydride (5 ml). A solution formed after several minutes, and stirring was continued overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was then extracted with 0.1N HCl, 1M sodium bicarbonate, and water and dried (MgSO4). Precipitation with hexanes gave 3.57 g (85.1%) of a solid melting at 113°-117° C. Recrystallization from ethyl acetate/hexanes gave 2.75 g, mp 118°-120° C., [α]D25 =+15.1° (c=2.1, ethanol).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cccc(Cl)c1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3c(Cl)cccc3Cl)CC2)c(OC)nc1C
Yield: 80 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,6-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20][CH2:19]1>CN1C(=O)CCC1.O>[N:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20][CH2:19]3)[N:7]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: Clc1nccc(-c2cnc3ccccn23)n1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-c3cnc4ccccn34)n2)CC1
Temperature: 105 °C
Reaction time: 10 h
Yield: 2.8 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.125 g), N-(4-amino-cyclohexyl)-methanesulfonamide (0.372 g), and TEA (0.38 mL) in NMP (3 mL) was stirred at 105° C. for 10 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid filtered, washed with water, and dried. The product was purified by ISCO using 100% DCM to 15% MeOH/DCM, the pure fractions combined and concentrated, then titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-[4-(4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (compound 10, 5.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[O:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:19]1
Reactant: O=C(O)c1ccoc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)cc23)CC1
Yield: 85.3 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.0 mg (0.15 mMol) 3-furoic acid, 13.8 mg (85%) of the title compound were recovered.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10]>C1C=CC=CC=1>[CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:10])[CH3:8].[C:1]1([CH:9]([CH3:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC
Reactant: Oc1ccccc1
Solvent: c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
The phenol producing apparatus 10, from an upstream side (the left side in the drawing), has a reaction tower 11 in which benzene reacts with propylene as raw materials to form so-called cumene isopropylbenzene, an oxidation tower 14 which oxidizes therein the cumene via a benzene tower 12 and a cumene tower 13 to form cumene hydroperoxide (CHP), a sodium removing apparatus 30 which separates and removes sodium mixed into for neutralization , a concentration tower 15 which concentrates cumene hydroperoxide, a sodium removing apparatus 31 provided on the way back from the concentration tower 15 to the upstream side of the oxidation tower 14, a disintegration tower 16 which disintegrates the concentrated cumene hydroperoxide by an acid material to form coarse phenol and coarse acetone, a sodium removing apparatus 32, and a coarse acetone tower 17, a refined acetone tower 18, a phenol tower 19 which are each kinds of distilled tower for separating and refining phenol and acetone.
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[CH2:21][CH3:22].[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]([C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC=O
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN(C1CCCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of (R)-3-(N-cyclopentylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran in methanol (25mL) were propanal (2 g, 36 mmol) and NaCNBH3 (2 g, 40 mmol) added. The solution was stirred overnight to give the desired compound in a 97% yield according to GC. The solvent was removed in vacuo and the residue was worked up by extraction to give 3.7 g of the title compound as a colorless oil. GC/MS (70 eV) M=307 (40% ).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[N:17]1[N:18]=[C:19]([SH:26])[N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12.CCN(C(C)C)C(C)C>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[N:18]=[C:19]([S:26][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12
Reactant: Sc1nnc2ccccn12
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1)C1CC1
Temperature: 120 °C
Yield: 187.2 %

Procedure:
N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (0.5 g, 1.52 mmol), [1,2,4]triazolo[4,3-a]pyridine-3-thiol (0.23 g, 1.52 mmol), Tris(dibenzylideneacetone)dipalladium(0) (84 mg, 0.09 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (106 mg g, 0.18 mmol), and DIEA (0.531 mL, 3.05 mmol) were dissolved in DME (15.2 mL) and heated in a microwave at 120° C. for 30 min. The reaction mixture was concentrated to dryness, reconstituted in DMSO, and purified by preparative LCMS to give N-(6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1 g, 43%) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ=11.17 (s, 1 H), 8.57-8.44 (m, 1 H), 8.03-7.94 (m, 1 H), 7.96-7.88 (m, 2 H), 7.59 (ddd, J=1.0, 6.6, 9.3 Hz, 1 H), 7.22-7.11 (m, 1 H), 7.11-7.03 (m, 1 H), 1.97-1.84 (m, 1 H), 0.83-0.73 (m, 4 H) ESI-MS:m/z 352.3 (M+H)+. MP 193-195° C.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])CO)=[O:7])(C)C.CC(OC([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=O)(C)C>>[CH:9]1([NH:8][C:6](=[O:7])[CH:25]([OH:26])[C@@H:24]([NH2:23])[CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Product: C[C@H](N)C(O)C(=O)NC1CCCC1
Yield: 45 %

Procedure:
The same reaction procedure as in Reference Example 12 was repeated except that (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanol used in Reference Example 12 was replaced by 14.33 g of (S)-2-[N-(2-methyl-2-propyloxycarbonyl) amino]propanol, whereby 6.95 g of the captioned (2RS,3S)-N-cyclopentyl-3-amino-2-hydroxybutanamide was obtained in a yield of 45%. 1H-NMR (CDCl3, δ): 1.05 (3/2H, d, J=7 Hz), 1.15 (3/2H, d, J=7 Hz), 1.35-1.50 (2H, m), 1.55-1.76 (4H, m), 1.90-2.10 (2H, m), 3.31-3.41 (1/2H, m), 3.48-3.52 (1/2H, m), 3.74 (1/2H, d, J=3 Hz), 3.87 (1/2H, d, J=5 Hz), 4.13-4.29 (1H, m), 7.18 (1/2H, d, J=8 Hz), 7.25 (1/2H, d, J=8 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].P([O-])([O-])([O-])=O>C1COCC1>[Si:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][OH:3])=[CH:7][CH:8]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Reaction time: 1.25 h
Yield: 71.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 145 mg) was added portionwise to a solution of 4-(2-hydroxyethyl)phenol (502 mg) in THF (15 ml) and the mixture was stirred at 20° C. for 30 min. tert-Butyldimethylsilyl chloride (547 mg) was added and the mixture was stirred for 75 min. Phosphate buffer solution (pH 6.5) was added and the mixture was extracted with EtOAc. The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by SPE (10 g). Elution with DCM-cyclohexane (1:3) then DCM then EtOAc gave the title compound (658 mg). LCMS RT=3.62 min.