Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OC2C(C3C4OCOC=4C=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2O1.O(C(C)(C)C)[Na].C1(C)C=CC=CC=1.[O:58]=[C:59]1[CH2:66][C:63]([CH3:65])([CH3:64])[CH2:62][C:61]([CH3:67])=[CH:60]1>CC(O)(C)C>[CH3:64][C:63]1([CH3:65])[CH2:62][CH:61]([CH3:67])[CH2:60][C:59](=[O:58])[CH2:66]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3c(c2-c2c(P(c4ccccc4)c4ccccc4)ccc4c2OCO4)OCO3)cc1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC1CC(=O)CC(C)(C)C1
Temperature: 50 °C
Reaction time: 17 h
Yield: 18 %

Procedure:
Into a 100-mL stainless-steel autoclave was put 22.6 mmol (0.03 mmol; Cu reduced) of the chiral copper complex [CuBr ((S)-SEGPHOS)]n obtained in the same manner as described in Example 1, 18.3 mg (0.03 mmol) of (S)-SEGPHOS and 28.8 mg (0.30 mmol) of NaO-t-Bu, followed by replacing with nitrogen in the autoclave, and then 2 mL of a mixed solvent of toluene and t-BuOH in a ratio of 3:1, and isophorone 1 (0.15 mL, 1 mmol) were added. The reaction was carried out with stirring under a hydrogen pressure of 5.0 MPa at 50° C. for 17 hours. The reaction mixture was analyzed by using GC. The results indicated that the products shown in the scheme A, that is, 3,3,5-trimethylcyclohexanone 2 was obtained in a yield of 18% (optical purity 93% ee), 3,3,5-trimethylcyclohexanol 3 was obtained in a yield of 61% (dr: 93/7, optical purity of main diastereomer: 95% ee), and 3,3,5-trimethyl-2-cyclohexenol 4 was obtained in a trace amount, respectively.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[C:12]([F:18])[CH:13]=[CH:14][C:15]=3[CH3:17])[C:10]3([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]3=4)[CH2:27][CH2:26][O:25]5)[C:9]2=[O:30])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[C:10]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:9](=[O:30])[NH:8]2
Reactant: Cc1ccc(F)c2c1N(C(c1ccccc1)c1ccccc1)C(=O)C21COc2cc3c(cc21)CCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: Cc1ccc(F)c2c1NC(=O)C21COc2cc3c(cc21)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: mp>250° C. (diethylether); 1H NMR (300 MHz, DMSO-d6) δ10.84 (s, 1H), 7.12-7.07 (m, 1H), 6.72-6.65 (m, 1H), 6.59 (s, 1H), 6.37 (s, 1H), 4.78-4.73 (m, 2H), 4.50 (t, J=8.7 Hz, 2H), 2.97 (d, J=8.7 Hz, 2H), 2.20 (s, 3H); MS (ES+) m/z 311.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][N:7]=[CH:6][C:5]=1Br.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][N:7]=[CH:6][C:5]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20]
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1c(Br)cncc1Nc1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(Nc2ccccc2F)cncc1-c1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
3-Bromo-5-(2-fluoro-phenylamino)-isonicotinic acid methyl ester (1.25 g, 3.84 mmol), 2-fluorophenylboronic acid (0.81 g, 5.77 mmol), Pd(OAc)2 (30 mg, 0.12 mmol), S-Phos (90 mg, 0.24 mmol), and K2CO3 (1.6 g, 11.5 mmol) were suspended in dioxane/H2O (9 mL, 9/1, v/v) and stirred overnight at 100° C. The reaction solution was diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the desired product (680 mg, 52%) as a yellow solid. LC-MS (M+H=341, obsd.=341).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39]>>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Clc1cccc(Cl)c1CBr
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2c(Cl)cccc2Cl)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-1,3-dichlorobenzene following the procedure of Example 478: MS (ESI) m/z 552.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:25][CH2:24][N:23]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:22][C:12]=3[N:13]=[C:14]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[N:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O>CO>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:25][CH2:24][N:23]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:22][C:12]=3[N:13]=[C:14]([O:16][CH2:17][C:18]([OH:20])=[O:19])[N:15]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Methyl 2-(4-(4-(trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yloxy)acetate (52.0 mg, 0.1 mmol) was suspended in MeOH (10 mL). NaOH (100 mg) and H2O (3 mL) were added and the mixture was stirred at 60° C. for 10 min. Solvent was removed, residue was dissolved in water, dilute HCl aqueous solution was added until a pH of 7 was obtained. Extracted by EtOAc, dried over Na2SO4 and the solvent was removed in vacuo, product was obtained as a white solid (47 mg).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[C:20]1([CH:26]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:27]([NH2:50])[CH:28]=[CH:29][S:30]([CH:33]=[CH:34][C@@H:35]([NH2:49])[CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:32])=[O:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:51]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:27]([NH:50][C:6](=[O:7])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:28]=[CH:29][S:30]([CH:33]=[CH:34][C@@H:35]([NH:49][C:6](=[O:7])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)(=[O:32])=[O:31])[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 98 %

Procedure:
Cbz-Val-Phe-VS-Ph was prepared from Cbz-Val-OH and Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 98%. 1H-NMR (CDCl3) δ 0.70-0.84 (2d, 6H, Val-CH3), 2.06 (m, 1H, Val-CH), 2.91 (m, 2H, CH2-Phe), 3.82 (m, 1H, α-H), 4.80-4.90 (m, 1H, α-H), 5.10 (s, 2H, Cbz), 5.96 (d, 1H, NH) 6.34 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph). MS (ESI) m/z 521 (M+1, 100%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8]1)[NH2:6]>O1CCOCC1>[CH3:1][NH:2][C:3]([NH:6][NH:5][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[N:8]=1)=[O:4]
Reactant: NNC1NS(=O)(=O)c2ccccc21
Reactant: CN=C=O
Solvent: C1COCCO1
Product: CNC(=O)NNC1=NS(=O)(=O)c2ccccc21
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 3.7 g (0.55 mol) of methyl isocyanate in 30 ml of dioxane is added dropwise to 9.8 g (0.05 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide in 100 ml of dioxane at room temperature. Stirring is continued for 1 hour, after which the product is filtered off under suction. 11.8 g (89% of theory) of 3-methylaminocarbonylhydrazino-1,2-benzisothiazole 1,1-dioxide of melting point 183° C. are obtained. The product can be recrystallized from ethanol.
Reaction SMILES: C1CCCCC1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13](=O)[CH2:14][CH:15]([CH3:17])[CH3:16]>O>[CH3:16][CH:15]([CH3:17])[CH:14]=[CH:13][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: CC(C)CC=O
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)C=CN1CCOCC1
Temperature: 50 °C

Procedure:
Into a 12 liter flask equipped with stirrer, Bidwell trap, thermometer, heating mantle, addition funnel and condenser is placed 2,200 ml of cyclohexane and 2,180 grams (25 moles) of morpholine. The resulting mixture is heated to 50° C. and 2,155 grams of isovaleraldehyde are added over a 1.5 hour period. An exotherm occurs and the solution begins to reflux. Additional heat is applied and the refluxing is continued until no additional water is collected in the Bidwell trap. The cyclohexane is then stripped off and the reaction product is distilled through a 1" stone packed column at total take-off yielding the following fractions:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13]CC)=[O:12])=[O:5])[CH3:2].[OH-].[Li+]>O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([OH:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@H]1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@@H]1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To a solution of rac-trans-cyclopentane-1,2-dicarboxylic acid diethyl ester (393 mg, 1.84 mmol) was added a solution of lithium hydroxide (75.5 mg, 1.8 mmol) in water (7 mL). The reaction mixture was stirred at room temperature for 30 minutes and then heated to 55° C. for 1 hr. The reaction mixture was cooled and evaporated under reduced pressure. The residue was dissolved in 25 mL water and washed with diethyl ether (2×5 mL). The pH of the aqueous layer was adjusted to pH 5 with 1N hydrochloric acid and extracted with methylene chloride (2×5 mL) and ethyl acetate (5 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give rac-trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester (95 mg) that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)O>O>[C:5]([C:4]1[C:3]([I:18])=[C:2]([C:10]([I:11])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:8]=1[I:17])[NH:1][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([OH:7])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)N(C)c1c(I)c(NC(=O)CCCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 58.6 g. of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 74 g. of glutaric anhydride and 8 ml. of concentrated sulfuric acid was heated on a steam bath for five hours. The reaction mixture was poured into water and the solid product collected by filtration. The product, consisting of 3-glutarimido-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid (Example 1) was dissolved in excess dilute aqueous sodium hydroxide, and the solution warmed for thirty minutes, then cooled and 3N hydrochloric acid added slowly until precipitation was complete. The solid product was collected and recrystallized first from acetone, then from acetic acid, and finally from water to give 3'-carboxy-5'-(N-methylacetamido)-2',4',6'-triiodoglutaranilic acid, colorless prisms, m.p. 188.8°-196.0° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:35]1[O:36][CH:37]=[CH:38][N:39]=1)CCC.O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH:37]=[CH:38][N:39]=[C:35]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-c4ncco4)ccnc23)CC1)c1ccccc1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
A mixture of compound of example 101 (30 mg, 0.074 mmol), 2-tributylstannanyl oxazole (106 mg, 0.30 mmol), Pd(PPh3)4 (129 mg, 0.112 mmol) and dioxane (1 mL) in a sealed tube was heated at 120° C. for 15 h. The reaction mixture was diluted with MeOH, filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (11.3 mg, 0.026 mmol, 39%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([NH:26][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(Br)c2)CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NCc3ccccc3)c2)CC1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
Under argon and dry conditions, 13.3 g (42.73 mmol) of tert-butyl 1-(3-bromobenzyl)-cyclopropanecarboxylate, 5.6 ml (51.28 mmol) of benzylamine, 1.96 g (2.14 mmol) of tris(dibenzylideneacetone)dipalladium, 4.93 g (51.28 mmol) of sodium tert-butoxide and 1.06 g (1.71 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were suspended in 50 ml of toluene. The reaction mixture was then stirred at 110° C. for 1.5 h. The mixture was then filtered off with suction through kieselguhr, the residue was washed with toluene and the filtrate was concentrated. The filtrate residue was taken up in ethyl acetate and washed twice with aqueous ammonium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 6.98 g (48.4% of theory) of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24].[C-]#N.[K+]>O>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=NOCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)=NOCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 85 °C

Procedure:
A mixture of 11.0 g of 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carbonitrile, 11.7 g of acetone (2-hydroxyethyl) oxime and 0.33 g of potassium cyanide is heated to 85° C. for 3 days. The reaction mixture, cooled to about 40° C., is treated with 100 ml of water and extracted twice with ethyl acetate. The extracts are washed three times with water and once each time with semi-saturated and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with acetone as the eluent, and there is obtained 2-[(isopropylideneamino)oxy]-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate as an oil, mass spectrum m/e: M+337 (13), 281 (11), 237 (72), 194 (84), 179 (79), 165 (78), 100 (85), 56 (100).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][CH2:23][CH:24]=[CH2:25]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:22][CH2:23][CH:24]=[CH2:25])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 162.6 %

Procedure:
A stirred and cooled (32° C.) mixture of 5.52 g (0.022 mole) of crude 3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 30 ml of tetrahydrofuran was treated with 1.5 g (0.02 mole) of 3-aminopropylene. The reaction mixture was still exothermic and was stirred for 5 hr as it cooled to ambient temperature. The reaction mixture was diluted with 200 ml of water to produce an oil phase separation. The oil portion was dissolved by extracting with 2×50 ml of benzene. The extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 8.14 g of orange-red oil. The oil partially crystallized from benzene-ligroin with charcoal treatment, yielding first a reddish oil followed by a crystalline product. The total material was concentrated in vacuo to yield 7.45 g of amber-red oil. This oil solidified and was repeatedly triturated with isopropyl ether until only a red oil residue remained. The isopropyl ether portions were repeatedly cooled to the crystallization of residue, decanted from residue and heated to reduce volume until only a straw colored isopropyl ether solution remained. Upon cooling of this solution the title product crystallized and yielded 2.3 g (42.3%) of white crystalline product, m.p. 92°-94° C.
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a stirred solution of 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.55 g, 1.58 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.32 g, 1.58 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.50 g, 88%) as a white solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.02-8.06 (m, 2H), 7.77 (s, 1H), 7.61 (m, 1H), 7.37 (dd, J=8.4, 1.5 Hz, 1H), 7.01 (m, 1H), 5.48 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].N>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(Cl)c12
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Intermediate 88 (375 mg) was dissolved in concentrated sulfuric acid (2 ml), then added with potassium nitrate (260 mg) with ice cooling and stirred for 2 hours. The reaction mixture was added with 28% aqueous ammonia (10 ml) and extracted twice with ethyl acetate (15 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (332 mg).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[CH3:30][S:31]([N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=2)[CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:18]3[N:17]=[CH:16][C:15]4=[CH:14][CH:13]=[C:12]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]([CH3:29])[S:2]([CH3:1])(=[O:3])=[O:4])[N:20]4[N:19]=3)[CH:42]=2)[CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: CS(=O)(=O)N1CCCc2ccc(N)cc21
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)N(S(C)(=O)=O)CCC4)nn12)S(C)(=O)=O

Procedure:
N-{2-[2-(1-Methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide was prepared from Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and 1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamine in an analogous manner to Example 1061. Product isolated as a yellow foam (61 mg, 55%). LCMS (m/e) 527 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 7.94-7.87 (m, 1H), 7.68-7.62 (m, 1H), 7.56-7.44 (m, 3H), 7.40 (dd, 1H, J=1.7 and 8.3 Hz), 7.00 (d, 1H, J=4.7 Hz), 6.96 (d, 1H, J=8.3 Hz), 6.87 (d, 1H, J=4.7 Hz), 6.79 (bs, 1H), 3.82-3.73 (m, 2H), 3.13 (s, 3H), 2.82-2.74 (m, 2H), 2.78 (s, 3H), 2.64 (s, 3H), 2.01-1.92 (m, 2H).