Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:47]1([CH2:50][NH:51][C:52]([C:54]2[N:55]=[C:56]([C:63]([F:66])([F:65])[F:64])[N:57]3[CH2:62][CH2:61][NH:60][CH2:59][C:58]=23)=[O:53])[CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:47]1([CH2:50][NH:51][C:52]([C:54]2[N:55]=[C:56]([C:63]([F:64])([F:65])[F:66])[N:57]3[CH2:62][CH2:61][N:60]([C:4](=[O:5])[C:3]4[CH:7]=[C:8]([CH2:11][C:12]5[C:21]6[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=6)[C:15](=[O:22])[NH:14][N:13]=5)[CH:9]=[CH:10][C:2]=4[F:1])[CH2:59][C:58]=23)=[O:53])[CH2:49][CH2:48]1
Reactant: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 30.3 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 24c (250 mg, 0.87 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 24 (150 mg, yield 30.0%) as a light yellow solid.
Reaction SMILES: [CH2:1]([C@@:3]1([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1)[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:16]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C@:3]([CH2:1][CH3:2])([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC[C@@]1(C(=O)OC)Cc2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC[C@@]1(C(=O)OC)Cc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step 4 (3.1 g, 15 mmol) was mixed with acetyl chloride (3.5 g, 45 mmol) and aluminum chloride (6.0 g, 45 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 25° C. for 1 hr and then poured into 1 N aqueous HCl (100 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined extracts were washed with brine and concentrated to give the title compound, which was used directly for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1nnccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnnc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 169.6 %

Procedure:
To a solution of ethyl 4-methylpyridazine-3-carboxylate (240 mg, 1.4 mmol) in H2O/THF was added 7.5 N aq. NaOH (1.25 eq, 0.25 mL) and the mixture was stirred for 1 hour at 60° C. Concentrated HCl was added to pH 2 and subsequently the volatiles were removed in vacuo. The residue was first stirred with EtOAc and the solids were collected by filtration then stirred with THF and the solids were again collected by filtration. The solids were extracted with MeOH and removal of the volatiles afforded 4-methylpyridazine-3-carboxylic acid (328 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:53]>CO.O1CCOCC1.ClCCCl>[ClH:1].[ClH:53].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCNC2CCCNC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-amino-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.065 g).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)#[N:7].[CH2:14]=[C:15]([CH3:17])[CH3:16].[OH-:18].[Na+]>C(O)(=O)C>[C:15]([NH:7][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=[O:18])([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: [OH-]
Reactant: N#Cc1cnccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.6 %

Procedure:
575 g (5.75 mmol) of sulfuric acid was added dropwise to 900 ml of acetic acid over 35 minutes at 20° C. (cooling), followed by 200.1 g (1.9 mol) of cyanopyrazine over 20 minutes. 142.4 g (2.54 mol) of isobutene was then introduced over 3.5 hours, the temperature being kept below 25° C. by appropriate cooling. The mixture was subsequently stirred for a further 2 hours at room temperature and then poured into 1.8 l of ice-water. The mixture was brought to pH 3.5 by the slow addition of 1527 g of 30 percent sodium hydroxide solution and then extracted continuously for 4 hours with 2.5 l of hot methylcyclohexane in a liquid-liquid extractor. The extract was cooled to 4° C., with stirring, and the product which had crystallized out was filtered off and dried under vacuum. The yield of the title compound was 246 g, content (titration): 99.6 percent. Concentration of the mother liquor gave a further 22.5 g of the title compound with a content of 99.0 percent. The total yield of the title compound was 268.5 g (78 percent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30](O)=[O:31].O.ON1C2C=CC=CC=2N=N1.Cl.[OH:45][CH:46]1[CH2:49][NH:48][CH2:47]1.Cl.C(/N=N/CCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:29][C:30]([N:48]1[CH2:49][CH:46]([OH:45])[CH2:47]1)=[O:31]
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Reactant: OC1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(2,6-difluoro-4-(2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetic acid (80 mg, 0.179 mmol), 1-hydroxybenzotriazole hydrate (41.1 mg, 0.268 mmol), 3-hydroxyazetidine hydrochloride (29.4 mg, 0.268 mmol) and (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (48.2 mg, 0.268 mmol) were dissolved in CH2Cl2 (4 ml). The mixture was stirred at RT for 5 min and triethylamine (0.075 ml, 0.536 mmol) was added. The mixture was stirred at RT overnight and purified by loading directly onto a Preparative TLC plate that was developed with pure EtOAc. The desired product (Rf=0.40 @ pure EtOAc) was collected to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 2H), 6.50 (d, 2H), 4.60 (m, 3H), 4.40 (m, 1H), 4.30 (m, 1H), 4.05 (m, 2H), 3.90 (m, 11-1), 3.80 (s, 3H), 3.41 (s, 2H), 3.05 (broad, s, 1H), 2.85 (m, 2H), 2.15 (m, 1H), 1.92 (m, 2H), 1.55 (m, 1H), 1.40 (m, 2H), 0.95 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 503 (M+H)+, GPR119 Human EC50: 0.59 nM.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (25 g, 0.12 mol) in ethyl acetate (400 ml) were added N-bromosuccinimide (21.4, 0.12 mol) and 2,2′-azobisisobutyronitrile (0.2 g) and the mixture was heated under reflux for 2.5 hrs. The reaction solution was concentrated under reduced pressure, and diethyl ether and hexane were added. Insoluble material was removed, and washed with diethyl ether. The filtrate was evaporated under reduced pressure to give 3-(1,1,2,2-tetrafluoroethoxy)-1-bromomethylbenzene. To a solution of ethyl 3-(4-bromophenyl)-3-oxopropanoate (27.1 g, 100 mmol) in dimethoxyethane (150 ml) was added sodium hydride (4.0 g, 60% in oil, 0.1 mol) under ice-cooling and the mixture was stirred for 1 hr. A solution of 3-(1,1,2,2-tetrafluoroethoxy)-1-bromomethylbenzene obtained above in dimethoxyethane (20 ml) was dropwise added and the mixture was stirred at room temperature for 15 hrs. To the reaction solution was added water (300 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:toluene=1:2-1:5). Crystallization from hexane gave the objective substance (21.1 g, 44%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH3:55])[C@H:28]([N:47]1[CH:51]=[C:50]([C:52]([NH2:54])=[O:53])[N:49]=[CH:48]1)[CH2:29][CH2:30][C:31]1[C:36]2[N:37]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[O:39][C:35]=2[CH:34]=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.CCOC(C)=O.O>C1COCC1>[ClH:46].[OH:26][C@@H:27]([CH3:55])[C@H:28]([N:47]1[CH:51]=[C:50]([C:52]([NH2:54])=[O:53])[N:49]=[CH:48]1)[CH2:29][CH2:30][C:31]1[C:36]2[N:37]=[C:38]([C:40]3[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=3)[O:39][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCc1cccc2oc(-c3ccc(Cl)cc3)nc12)n1cnc(C(N)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@@H](CCc1cccc2oc(-c3ccc(Cl)cc3)nc12)n1cnc(C(N)=O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
1M solution of tetrabutylammonium fluoride in THF (0.387 ml) was added to a solution of 1-{(3R,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-3-pentyl}imidazole-4-carboxamide (E0001; 0.16 g) in THF (7 ml) and the mixture was stirred at r.t. for 2 hours. EtOAc and water were added and the organic layer was separated, washed with water, dried and evaporated. The residue (0.16 g) was chromatographed over silica gel (5 g) eluting with a mixture of dichloromethane and methanol (20:1 to 10:1). The desired product was treated with HCl in EtOAc to give a white powder of 1-{(3R,4S)-4-hydroxy-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-3-pentyl}imidazole-4-carboxamide hydrochloride (E0017; 79.4 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:3]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](Cl)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2([C:27](=[O:28])[CH2:26][C:21]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:3]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: OC1CCN(CC2NCCc3ccccc32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCC(O)C2)NCCc2ccccc21

Procedure:
Prepared as Example n° 1 from 5.0 g (21.5 mmoles) of 1-(3-hydroxypyrrolidin-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline--diast. mix.--, 5.2 g (23.6 mmoles) of 3,4-dichlorophenylacetyl chloride and 3.6 g (23.6 mmoles) of anhydrous potassium carbonate.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH3:13]O.S(=O)(=O)(O)O>O>[CH3:13][O:11][C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([OH:9])=[O:8])=[CH:6][N:1]=1)=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cn1

Procedure:
A mixture of pyridine-2,5-dicarboxylic acid (8.4 g), methanol (100 ml) and concentrated sulphuric acid (1.7 ml) was heated at reflux for 2 hours, cooled and poured into water (11). The resultant precipitate was collected and recrystallised from ethanol to give the title compound as a white solid, m.p. 222-223° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:31])[CH3:30])[S:7][C:6]=2[CH:32]=1.[Li+].[OH-].Cl>CCO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:30])[CH3:31])[S:7][C:6]=2[CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O)ccc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Yield: 96.6 %

Procedure:
Example 4 was be prepared from the corresponding methylether/tert-butyl ester intermediates using method A. Example 4 was also prepared, using the following hydrolysis reaction: to a solution of (E)-methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (25.8 mg, 0.058 mmol) in EtOH (1.5 mL) was added LiOH (2.0 M aqueous, 0.290 mL, 0.580 mmol). After 5 h at room temperature the reaction was acidified to pH 3 by addition of 1.0 N aqueous HCl and extracted with 5% MeOH/EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to afford (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (24.0 mg, 0.056 mmol, 96% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.57 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.37-7.21 (m, 5H), 7.15-7.08 (m, 1H), 6.88-6.82 (m, 3H), 6.31 (d, J=15.9 Hz, 1H), 3.27-3.18 (m, 1H), 1.16 (d, J=6.8 Hz, 61). LC/MS (m/z, M−H): 429.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:13]2[CH2:12][CH2:11][N:10]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=3)[CH2:15][CH2:14]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Yield: 94.8 %

Procedure:
Using 1-(3,5,6-trimethylpyridin-2-yl)piperazine (4.39 g) described in Preparation Example 92 and 4-iodobenzoyl chloride (5.98 g) and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (8.82 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C(OC([N:46]1[CH2:51][CH2:50][CH:49]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([NH:61][C:62]3[N:67]=[CH:66][C:65]([NH2:68])=[CH:64][N:63]=3)=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:48][CH2:47]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:68][C:65]1[CH:66]=[N:67][C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([S:52]([CH:49]3[CH2:50][CH2:51][NH:46][CH2:47][CH2:48]3)(=[O:53])=[O:54])=[CH:56][CH:57]=2)=[N:63][CH:64]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(Cl)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
Intermediate 19 (Example 27) (0.136 g, 0.44 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were diluted with DCM (4 mL) and treated with TFA (0.2 mL). After 2 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.030 g, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].Br.CS(C)=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCOCC2)cc1NC(N)=S
Agent: Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2CCOCC2)c2sc(N)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a stirred solution of 1.90 g (7.13 mmol) [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea in 20 ml acetic acid heated to 80° C. was added dropwise 1.45 ml (8.27 mmol) hydrobromic acid (5.7 M solution in acetic acid) and stirring continued for 30 min at 80° C.0.56 ml (7.85 mmol) DMSO was then added dropwise and the reaction mixture stirred for a further 30 min at 80° C. The mixture was then cooled to room temperature, poured slowly onto sodium bicarbonate solution, and ethyl acetate added. The mixture was stirred for 10 minutes at room temperature and the resulting crystals collected by filtration, washing with ethyl acetate. The mother liquor phases were separated and the organic phase concentrated in vacuo to 5 ml. The resulting second crop of crystals was collected by filtration and combined with the first crop to afford 920 mg (49%) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 265 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(Br)cc1
Product: O=[N+]([O-])c1cc(NCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Yield: 73 %

Procedure:
A solution of the product from Example 84A and 4-Bromobenzaldehyde were reacted according to the procedure from Example 84B substituting 4-Bromobenzaldehyde for the product from Example 84A to provide the crude product which was purified by silica gel chromatography eluting with 2% methanol in methylene chloride to provide the title compound as a yellow solid (0.11 g, 73%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>CCO>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[NH:2][N:3]=[CH:4]3)[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3[nH]ncc3c2)n1
Yield: 60 %

Procedure:
A mixture of (1H-indazol-5-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo-pentanenitrile (19 g, 1.05 eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-amine (23 g, 60% of two steps). 1H NMR (300 MHz, DMSO-d6): 8.24 (s, 1H), 8.06 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.45 (dd, J=9.0 Hz, 1.8 Hz, 1H), 5.7 (s, 1H), 1.31 (s, 9H). MS (ESI) m/z: 256 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1.[NH2:21][NH2:22]>C1COCC1>[N:15]1([C:4]2[N:5]=[C:6]([O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[N:7]=[C:2]([NH:21][NH2:22])[CH:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Reactant: NN
Solvent: C1CCOC1
Product: NNc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
To a solution of 4-[6-chloro-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-morpholine (295 mg, 1 mmol) in THF (10 mL) was added anhydrous hydrazine (0.320 ml, 10 mmol) under the nitrogen protection. The mixture was heated at 70° C. for 15 min. After cooling to room temperature, the reaction mixture was quenched by ice brine and extracted with EtOAc (100 mL). The organic phase was washed with brine (10 mL) and water (10 ml×2), dried (Na2SO4), filtered, evaporated, and purified by flash chromatography on a column of silica gel (CH2Cl2 and CH2Cl2-MeOH, 95:5) and to give [6-morpholin-4-yl-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-hydrazine (180 mg) in 62% yield. M/Z (M+1) 289.2
Reaction SMILES: CN(C)[C:3]([CH3:17])=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.C([O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=1)(C)(C)C.C(OC(=O)C1C=CC=C(C(=N)N)C=1)(C)(C)C.[H-].[Na+]>C(O)C>[CH3:17][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=2)[N:32]=[C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([OH:23])=[O:34])=[CH:30][CH:29]=2)[N:33]=1
Reactant: CC(=CC(=O)c1ccc(C(F)(F)F)cc1)N(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(C(=N)N)cc1
Agent: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(=O)O)cc2)n1
Yield: 2.7 %

Procedure:
Part B. To a mixture of 3-dimethylamino-1-(4-trifluoromethyl-phenyl)-but-2-en-1-one (290.1 mg, 1.13 mmol), 4-carbamimidoyl-benzoic acid tert-butyl ester (220.3 mg, 1.00 mmol, prepared by the same manner as 3-carbamimidoyl-benzoic acid tert-butyl ester) and sodium hydride (79.9 mg, 2.00 mmol, 60% in hexanes) is added dry ethanol (5.0 mL). The resulting mixture is stirred at refluxing for 14 h until complete consumption of the starting material is determined by TLC. The solvent is removed, and the residue is neutralized with 1N HCl until pH <7 to precipitate a white solid, which is collected by filtration followed by washing with water and ethyl ether/hexanes (1:1). The obtained solid is further purified by flash column chromatography, eluting with methanol/methylene chloride (1:40), to give the title product (10.7 mg, 2.7% yield), m.p. 272-275° C. 1H NMR (300 MHz, CDCl3+2 drops DMSO-d6): δ 8.54 (2H, d, J=8.3 Hz), 8.23 (2H, d, J=8.6 Hz), 8.09 (2H, d, J=8.3 Hz), 7.71 (2H, d, J=8.6 Hz), 7.48 (1H, s), 2.61 (3H, s). MS (ES+): m/e 359.27.