Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.[NH:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:16]3[CH2:19][CH:18]([OH:20])[CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Yield: 81.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), azetidin-3-ol hydrochloride (3.01 g, 27.50 mmol) and DIPEA (10.89 mL, 62.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was slowly diluted with water and the product crystallised. The precipitate was collected by filtration, washed with water, drained well and washed with ether. It was dried under vacuum to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]azetidin-3-ol (5.30 g, 82%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:32](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:32][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNCCc5cccs5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCCc5cccs5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 73.5 %

Procedure:
[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylethylamine is prepared as described in Example 179a starting with 0.15 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylethylamine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1.12 cm3 of 5N potassium hydroxide. 0.082 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylethylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][NH2:6])=[O:4].[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Cl:9][CH2:10][C:11]([NH:6][NH:5][C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])=[O:12]
Reactant: CC(C)(C)C(=O)NN
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NNC(=O)CCl

Procedure:
5.8 g (49.929 mmol) of 2,2-dimethylpropanehydrazide were dissolved in 600 ml of dry ethyl acetate and heated to reflux. 6.767 g (59.915 mmol) of chloroacetyl chloride, dissolved in 45 ml of dry ethyl acetate, were added dropwise to the solution. The mixture was stirred under reflux for 30 min. After cooling, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 10.14 g of the title compound. The crude product was reacted further without further purification.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=O)C.[Se](=O)=[O:34]>C(OCC)(=O)C.CCCCCC>[OH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (120 mg, 0.27 mmol) was added selenium dioxide (120 mg, 1.08 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-hydroxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (40 mg, 37% yield).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccco4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.650 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-furoyl chloride (0.290 g, 2.22 mmol) was added and the mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-furylcarboxamide (0.51 g, 73%) as a white solid: mp 121–123° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 9.01 (t, J=5.7 Hz, 1H), 7.88–7.68 (m, 4H), 7.18 (d, J=3.3 Hz, 1H), 6.66 (m, 1H), 5.20–5.13 (dd, J=5.4 and 12.5 Hz, 1H), 4.90 (d, J=5.6 Hz, 2H), 2.97–2.84 (m, 1H), 2.65–2.49 (m, 2H), 2.10–1.98 (m, 1H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.52, 166.94, 158.09, 147.49, 145.27, 139.06, 134.80, 132.98, 131.52, 127.09, 121.88, 113.86, 111.91, 48.86, 37.64, 30.92, 21.97; Anal. Calcd. For C19H15N3O6+0.18 H2O: C, 59.34; H, 4.03; N, 10.93. Found: C, 59.47; H, 4.16; N, 10.49.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:20])[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)C(=O)OC(C)(C)C.[ClH:21]>C(Cl)Cl>[ClH:21].[ClH:21].[CH3:20][N:12]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:11][CH2:10][NH:2][CH3:1]
Reactant: Cc1cncc(N(C)CCN(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Product: CNCCN(C)c1cncc(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
tert-Butyl N-methyl-N-[2-[methyl-(5-methyl-3-pyridyl)amino]ethyl]carbamate (301 mg, 1.078 mmol) was dissolved in DCM (40 ml). Hydrochloric acid (4M in dioxane, 5.4 ml) was added and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure, diethylether was added and the mixture was stirred at room temperature for 4 days. The solids were collected by filtration, rinsed with diethylether and dried under reduced pressure to yield 199 mg (0.789 mmol, 73%) MS(ESI) m/z=180.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to preparation 3, react 4-aminobenzeneacetic acid, methyl ester with methanesulfonyl chloride, and pyridine to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([O:29]COC)[CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[F:28])=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.Cl.CO.C1COCC1>>[NH2:1][C:2]1[C:10]2[C:5](=[C:6]([OH:29])[CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[F:28])=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1
Reactant: COCOc1ccc(-c2ccc(NC(=O)Nc3cc(C)ccc3F)cc2)c2c(N)n[nH]c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccc(O)c4[nH]nc(N)c34)cc2)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
A mixture of Example 119B (90 mg) and a 1:1:1 mixture of 3N HCl/methanol/THF (3 mL) was heated to 50° C. for 3 hours, concentrated to half its original volume, and partitioned between saturated NaHCO3 and ethyl acetate. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 30 mg of the desired product. MS (ESI(+)) m/e 392 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.25 (s, 2H), 6.60 (d, J=5.76 Hz, 2H), 6.82 (m, J=5.09, 3.05 Hz, 1H), 7.11 (m, 2H), 7.33 (d, J=8.48 Hz, 1H), 7.54 (d, J=8.81 Hz, 2H), 8.01 (dd, J=7.97, 2.20 Hz, 1H), 8.51 (d, J=2.71 Hz, 1H), 9.14 (s, 1H), 9.84 (s, 1H), 11.58 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH2:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCC3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and indan-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7](Cl)=[CH:8][CH:9]=2)[N:4]=1.P(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: BrCc1ccc2ccccc2n1
Yield: 13.8 %

Procedure:
A magnetically stirred solution of 2-bromomethyl-7-chloroquinoline (1.0 g, 3.91 mmol) and triethyl phosphite (0.74 g, 4.45 mmol) in dry toluene (10.0 ml) was heated under reflux for 24 h. The cooled solution was adsorbed onto a quantity of silica (ca. 5.0 g) and column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) provided unreacted 2-bromomethylquinoline (0.12 g, 0.469 mmol-12%) as brown crystals. Further elution (ethyl acetate) secured the title compound (0.88 g, 72%) as a yellow/brown oil. Distilled at 240° C. at 0.05 mmHg using a Kugelrohr short-path distillation apparatus as a bright yellow oil which crystallised on standing (m.p. 33-37° C.); (Found: C, 53.17; H, 5.40; N; 4.31; Cl, 11.22. C14H7ClNO3P requires C, 53.6; H, 5.46; N, 4.46; Cl, 11.3%); νmax (thin film)/cm−1 3060.5, 2981.5, 1612.5, 1598.5, 1559.5. δH (270 MHz) 1.27 (6H, t, 2×CH2CH3, 3J=6.9 Hz); 3.60 (2H, d, CH2P, 2J=22.4 Hz); 4.11 (4H, m, 2×CH2CH3); 7.47 (1H, dd, 3-H, Jo=7.0, 4J3H.P=0.8 Hz); 7.51 (1H, dd, 6-H, Jo=8.4, Jm=1.5 Hz); 7.72 (1H, d, 5-H, Jo=8.9 Hz); 8.05 (1H, d, 8-H, Jm=1.7 Hz); 8.06 (1H, d, 4-H, Jo=8.3 Hz). δc (67.8 MHz) 16.15 (CH2CH3, d, 3JC.P=6.1 Hz); 37.0 (CH2P, d, 1JC.P=134.3 Hz); 62.3 (CH2CH3, d, 2JC.P=6.1 Hz); 122.3 (3-C, d, 3JC.P=2.5 Hz), 125.1 (4a-C), 135.3 (7-C), 136.2 (4-C); 147.9 (8a-C), 154.3 (2-C, d, 2JC.P=8.6 Hz). Remaining 315.3, 313.2 (7.52, 22.18, M+), 277.3 (2.21), 242.1, 240.1 (1.79, 5.13), 193.1 (6.84), 179.1, 177.1 (33.1, 100), 142.2 (3.65), 109.1 (4.57).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1.Cl>CO.C1COCC1.CCOCC.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[ClH:1].[NH2:36][CH2:35][C:20]1[N:19]=[C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=3)=[C:12]([F:37])[CH:13]=2)[C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[O:25])=[CH:22][N:21]=1
Reactant: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)n1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: NCc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)n1
Reaction time: 2 h
Yield: 110.4 %

Procedure:
To a solution of 4-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-2-cyano-N-(2,4-difluorophenyl)pyrimidine-5-carboxamide, dihydrochloride salt (48 mg, 0.092 mmol) in methanol (1 mL) was added 1 N HCl in ether (30 μL, 0.03 mmol), and 20% palladium hydroxide on carbon (48 mg). The suspension was purged with hydrogen and was stirred 2 h. Additional palladium hydroxide (38 mg) and methanol (1 mL) was added and the mixture was stirred an additional 4 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and treated with Amberlyst A-21 ion exchange resin, filtered and concentrated in vacuo to give the freebase. The residue was dissolved in anhydrous THF (2 mL), and acidified with 1N HCl in ether. The reaction mixture was stirred for 10 min, the solvent was removed in vacuo and the solid was triturated in ether to afford the amine (20 mg, 39%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.99 (s, 1H), 10.78 (s, 1H), 9.16 (s, 1H), 8.48 (br s, 2H), 8.17 (dd, 1H, J=12.9, 2.4 Hz), 7.99 (d, 1H, J=7.2 Hz), 7.87 (br s, 2H), 7.62 (m, 2H), 7.43 (m, 2H), 7.20 (m, 1H), 6.70 (dd, 1H, J=7.2, 2.4 Hz), 6.21 (d, 1H, J=2.3 Hz), 4.21 (m, 2H); MS(ESI+) m/z 482 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19](C2C=NC=CC=2)[CH3:20])=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][C:30](C(N)C)=[CH:29][CH:28]=1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH3:20])=[CH:5][CH:4]=1
Reactant: CC(N)c1ccncc1
Reactant: COc1ccc(-c2cc(CNC(C)c3cccnc3)ccc2OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [Na+]
Product: COc1ccc(-c2cc(CNC(C)c3ccncc3)ccc2OC)cc1
Yield: 51 %

Procedure:
The title compound was prepared by the same procedure for preparing (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-pyridin-3-yl-ethyl)-amine from 1-Pyridin-4-yl-ethylamine (245 mg, 2 mmol), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (121 mg, 0.5 mmol) and sodium triacetoxyborohydride (212 mg, 1.0 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 51% yield (89 mg, 0.26 mmol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:22]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:23]5[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=5)=[CH:32][CH:31]=4)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cnc(O)nn23)cc1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)cc1

Procedure:
[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (37 mg, 28%). LCMS (m/e) 442 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.82 (s, 1H), 9.10 (s, 1H), 8.94 (s, 1H), 8.58-8.46 (m, 3H), 8.17-8.05 (m, 3H), 7.90 (d, 2H, J=7.9 Hz), 7.76 (d, 2H, J=7.9 Hz), 7.54-7.44 (m, 1H), 7.44-7.35 (m, 1H), 7.09-7.01 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:21][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:37][C:38]([OH:55])([CH3:54])[CH2:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>>[C:31]([Si:28]([CH3:29])([CH3:30])[O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:43]6[CH:42]=[N:41][N:40]([CH2:39][C:38]([CH3:54])([OH:55])[CH3:37])[CH:44]=6)[CH:36]=[CH:35][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:24][CH2:23]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 1-{4-[2-(2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol. MS (ESI+) 650.3
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1.Cl[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[O:6]1[CH2:7][CH2:8][C@H:4]([O:3][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:5]1
Reactant: ClCc1ccccn1
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CO[C@H]2CCOC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A 3-neck flask under a nitrogen-line was charged with anhydrous THF (600 mL) through a canule. NaH (60% dispersion in mineral oil, 21.16 g, 0.529 mol, 1.5 eq) was suspended in the solvent under vigorous stirring. (S)-(+)-3-hydroxytetrahydrofuran (34.14 g, 0.388 mol., 1.1 eq) was added and stirred at room temperature for 30 minutes. 2-Chloromethylpyridine (1a; 45.00 g, 0.353 mol, 1 eq) was added neat and the mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature and quenched with 520 mL saturated aqueous ammonium chloride solution. THF was removed under reduced pressure and the aqueous residue was extracted with 2×800 mL ethyl acetate. The combined organic extracts were washed with 250 mL saturated brine, dried over Na2SO4 and evaporated to dryness. The brown oily residue was taken up in 520 mL acetonitrile and remaining mineral oil was extracted with 330 mL hexane. Acetonitrile was evaporated in vacuo to leave a brown residue, yield 87%; LC-MS Retention time 1.22 min; (M+H)+ 180.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([S:11][C:12]([F:15])([F:14])[F:13])=[C:9]([CH3:16])[N:8]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=[O:32].OO>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([S:11]([C:12]([F:15])([F:13])[F:14])=[O:32])=[C:9]([CH3:16])[N:8]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(C)c1SC(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(C)c1S(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethylsulfanyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g, 2.7 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.4 mL) at 0° C. To the reaction mixture was added an aqueous solution of hydrogen peroxide (30 wt %, 0.9 g, 8.3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 6 h. The reaction was quenched by addition of a solution of sodium bisulfite (0.8 g) in water (12 mL). The resulting mixture was extracted with dichloromethane. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography, elution with heptanes/EtOAc, to give 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (1.2 g, 2.6 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.1 Hz, 3H), 2.51 (s, 3H), 4.36-4.55 (m, 2H), 7.54 (dd, J=8.3, 1.6 Hz, 1H), 7.72 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −113.2 (d, J=7.9 Hz, 0.5F), −112.8 (d, J=9.2 Hz, 0.5F), −74.0 (s, 1.5F), −73.8 (s, 1.5F), −63.8 (s, 3F).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].CN1CCCN(C)C1=O>C1COCC1>[CH2:16]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc2cc(O)cnc2cc1OC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1cc2cc(OCc3ccccc3)cnc2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-hydroxy-6,7-dimethoxyquinoline (150 mg; 0.73 mmol) in 3 mL THF is added benzyl bromide (0.13 mL; 188 mg; 1.10 mmol) and Nail (59 mg; 1.46 mmol). This is stirred at room temperature for 1 hour and 25 mg of NaH added followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU)(255 mg; 2.07 mmol) and stirred at room temperature for 31/2 hours. The reaction mixture is partitioned between EtOAc and distilled H2O and extracted 2× with EtOAc. The latter is washed with brine, dried (MgSO4), filtered, evaporated to dryness and chromatographed with 1% MeOH/CHCl3 to obtain 3-benzyloxy-6,7-dimethoxyquinoline m.p. 146.5°-148.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
In one portion, 96 g (0.75 mole) of 4-chlorophenol was added to a stirred solution of 67.5 ml (0.75 mole) of chlorosulfonylisocyanate in 400 ml of toluene. The solution was heated at 100° C. for 16 hr and the solution chilled with an ice-acetone bath and water added dropwise until evolution of gases ceased. The tan solid which precipitated from solution was collected and dried for 16 hr to yield 133.4 g. A 25 g portion was recrystallized from 100 ml of toluene to give 15.8 g of white solid, mp 103°-104° C.