Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]CC)(=O)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:1][CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CC=CCC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A solution of ethyl hexa-3,5-dienoate (4.0 g, 28.6 mmol) in dry tetrahydrofuran (200 mL) was treated with a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 28.6 mL, 28.6 mmol). The mixture was stirred at room temperature for 2 hours, and then quenched with water. The mixture was acidified with 1.0 N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to a yellow oil. 1H NMR (300 MHz, CDCl3) δ6.4-6.1 (m, 2H), 5.67 (m, 1H), 5.13 (d, J=17 Hz, 1H), 5.00 (d, J=11 Hz, 1H), 3.66 (t, J=6.6 Hz, 2H), 2.34 (q, J=6.6 Hz, 2H), 2.13 (broad s, 1H). The oil was dissolved in dichloromethane, cooled to 0° C. and treated with pyridine (10 mL) and p-toluenesulfonyl chloride (5.72 g, 30 mmol). The mixture was stirred for one hour, then warmed to room temperature and stirred for 3 hours. The mixture was then concentrated, and the residue was dissolved in ethyl acetate, washed sequentially with water, 1.0 N aqueous hydrochloric acid, 1.0 N aqueous sodium hydroxide, and saturated aqueous sodium chloride, then was dried over magnesium sulfate and concentrated to provide a yellow oil. This yellow oil was purified by flash column chromatography, eluting with 10% ethyl acetate/hexane, to give a colorless oil (3.84 g, 53%). 1H NMR (300 MHz, CDCl3) δ7.78 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 6.22 (td, J=17, 10 Hz, 1H), 6.04 (dd, J=11, 10 Hz, 1H), 5.10 (d, J=17 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 4.05 (t, J=7 Hz, 2H), 2.44 (s+m, 5H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4](=[O:25])[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:36][C:37]1[CH:38]=[C:39]([C:45]2([C:48]#[N:49])[CH2:47][CH2:46]2)[CH:40]=[C:41]([CH:43]=O)[CH:42]=1>C1COCC1>[Br:36][C:37]1[CH:42]=[C:41](/[CH:43]=[CH:5]/[C:4]([O:3][CH3:2])=[O:25])[CH:40]=[C:39]([C:45]2([C:48]#[N:49])[CH2:47][CH2:46]2)[CH:38]=1
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CC1(c2cc(Br)cc(C=O)c2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(Br)cc(C2(C#N)CC2)c1
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a suspension of (2-methoxy-2-oxo-ethyl)-triphenyl-phosphonium bromide (1.502 g, 3.618 mmol) in THF (15 mL) under nitrogen at room temperature was added LHMDS in THF (3.358 mL of 1 M, 3.358 mmol) dropwise. The mixture was stirred for 10 mins then cooled to −25° C. 1-(3-bromo-5-formyl-phenyl)cyclopropane-1-carbonitrile (500 mg, 1.999 mmol) was dissolved in 1 mL of THF and added to the reaction. The reaction was allowed to warm to room temperature over 1 hour. The reaction was quenched with MeOH (2 mL) and then partitioned between ethyl acetate and brine. The aqueous was extracted with ethyl acetate and dried, filtered and concentrated. The crude product was purified on silica (Companion, 24 g) eluting with 1-20% EtOAc:Petrol ether to give methyl (E)-3-[3-bromo-5-(1-cyanocyclopropyl)phenyl]prop-2-enoate as a yellow solid (594 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[N:14][CH3:15])[CH:7]=[CH:6]2.[BH4-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][NH:14][CH3:15])[CH:7]=[CH:6]2
Reactant: CN=Cc1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1ccc2cc(OC)ccc2c1
Reaction time: 18 h
Yield: 93.4 %

Procedure:
(6-Methoxy-naphthalen-2-ylmethylene)-methyl-amine (20.0 g, 100 mmol), prepared in the previous step, was dissolved with heating in 300 mL of absolute ethanol. At room temperature, sodium borohydride (3.783 g, 100 mmol) was added portion wise. The reaction stirred under nitrogen for 18 h. 1N HCl was added to the reaction until pH 1 (litmus paper). The solvent was removed under reduced pressure and the resulting residue was partitioned between methylene chloride and water. The aqueous layer was made basic with 1N NaOH. The aqueous layer was separated and extracted with methylene chloride. The combined organic extracts were dried (MgSO4) and solvent removed under reduced pressure to give (6-methoxy-naphthalen-2-ylmethyl)-methyl-amine (18.80 g, 93.5%) as an off-white solid, mp 96-104° C.
Reaction SMILES: CC[O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=O.O=[C:17]([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[OH-].[Li+].[BH4-].[Li+].[Cl-].[NH4+]>C1COCC1>[F:7]/[C:6](/[CH2:4][OH:3])=[C:17](\[CH3:27])/[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(CNC(=O)OC(C)(C)C)=C(\F)CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
A mixture of triethyl 2-fluoro-2-phosphonoacetate (1.07 mL, 5.2 mmol), tert-butyl (2-oxopropyl)carbamate (0.865 g, 5.0 mmol) and lithium hydroxide (0.21 g, 5.0 mmol) in THF (15 mL) was at room temperature for 16 hours. The mixture was cooled to 0° C. and lithium borohydride (0.22 g, 10.0 mmol) was added in portions. Stirring was continued at 0° C. for 1 hour and at room temperature for 2 hours. Saturated ammonium chloride solution (25 mL) was added to the mixture and the organic layer extracted with ethyl acetate (50 mL) and washed with brine (20 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the crude product as a clear oil (0.90 g). Purification by flash chromatography eluting in 20% EtOAc in n-hexane afforded tert-butyl [(2E)-3-fluoro-4-hydroxy-2-methylbut-2-en-1-yl]carbamate (0.33 g, 30%) as white solid. 1H-NMR (400 MHz, CDCl3): δppm: 1.42 (9H, s), 1.68 (3H, d, J 3.2 Hz), 3.67 (2H, dd, J 6.4, 1.2 Hz), 3.80 (1H, t, J 6.4 Hz), 4.26 (2H, dd, J 24.8, 6.4 Hz), 4.98 (1H, brs).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.Cl[CH2:26][C:27](=[O:29])[CH3:28]>>[Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][N:11]([CH2:26][C:27](=[O:29])[CH3:28])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Yield: 27.3 %

Procedure:
Prepared by the method described for example 26 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.6 g, 0.006 moles), triethylamine (1 ml, 0.007 moles) and 1-chloro-2-propanone (0.57 g, 0.006 moles). Recrystallization from isopropanol gave the product (0.5 g), mp 172°-175° C.
Reaction SMILES: C1COCC1.[BH4-].[Na+].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1)([O-])=O>CO.[Ni](Br)Br>[NH2:8][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CNc2ccccn2)cc1
Agent: Br[Ni]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CNc2ccccn2)cc1
Yield: 46.1 %

Procedure:
To a solution of nicke l bromide (44 mg) in methanol (4 ml)/THF (4 ml) was added sodium boro hydride (40 mg), and the mixture was stirred. To the mixture was added 2-[(4-nitrophenyl)methylamino]pyridine (0.92 g) and then sodium boro hydride (414 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added nickel bromide (44 mg)and sodium boro hydride (454 mg), and the mixture was stirred at room temperature for 2 hours. Insoluble materials were filtered off with sellaite, and to the filtrate was added sodium bicarbonate solution. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried (anhydrous magnesium sulfate) and concentrated, and the residue was purified twice with silica gel column chromatography (ethyl acetate/hexane=1/1) to give 2-[(4-aminophenyl)methylamino]pyridine (369 mg) as pale red solid.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][C@H:8]([C@H:10]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C@:11]1([CH3:21])[CH2:12][CH2:13][CH2:14][C:15]2=[O:20])[CH3:9].[Si:24](C1NC=CN=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:9][C@@H:8]([C@H:10]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C@:11]1([CH3:21])[CH2:12][CH2:13][CH2:14][C:15]2=[O:20])[CH2:7]/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[C:2]([CH3:22])([O:1][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH3:23]
Reactant: C[C@H](C/C=C/C=C/C(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: ClCCl
Product: C[C@H](C/C=C/C=C/C(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C

Procedure:
323 mg of (4aR,5R,8aR)-5-((3E,5E)-(R)-7-hydroxy-1,7-dimethyl-octa-3,5-dienyl)-4a-methyl-octahydro-naphthalen-1-one, was reacted at 40° with 1.33 ml of TMS-imidazole (9 equivalents) in 8 ml of CH2Cl2. After a few hours the mixture was poured onto crushed ice, extracted with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) yielded 326 mg of (4aR,5R,8aR)-5-[(3E,5E)-(R)-(1,7-dimethyl-7-trimethylsilanyloxy-octa-3,5-dienyl)]-4a-methyl-octahydro-naphthalen-1-one as colourless oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12]C=[C:14](C(C4C=CC=CC=4)=O)[CH:15]=3)[C:10]([CH3:25])=[CH:9]2)=CC=1.[BH4-].[Na+].[OH2:30]>>[CH3:14][C:15]1[CH:16]=[N:8][CH:9]=[C:10]([CH3:25])[C:11]=1[CH2:12][OH:30]
Reactant: O
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)c4ccccc4)cc32)cc1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cncc(C)c1CO
Reaction time: 6 h

Procedure:
A stirred solution of 3,5-dimethyl-pyridyl-4-carbaldehyde (2.3 g, Reference Example 24) in methylated spirit (50 ml), at room temperature and under nitrogen, was treated with powdered sodium borohydride (1.28 g). After stirring for 6 hours the resulting homogeneous solution was allowed to stand at room temperature for a further 12 hours then treated with water (10 ml). The reaction mixture was evaporated, then azeotroped with toluene. The residue was extracted three times with hot dichloromethane (100 ml). The combined extracts were evaporated to afford a white solid which was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to afford the title compound (1.2 g) as a white solid, m.p. 93-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH:16][NH2:17]
Reactant: NN
Reactant: Fc1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Solvent: O
Solvent: CCO
Product: NNc1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
470 g (1.87 mol) of 3,5-dichloro-2,4-difluorobenzotrifluoride are initially introduced in 1000 ml of ethanol, 142 g (2.84 mol) of hydrazine hydrate are metered in, and the mixture is subsequently heated to reflux for 3 hours. The solvent is then removed by distillation under reduced pressure, and the residue is stirred into 1000 ml of cold water. After 30 minutes, the solid product is filtered off with suction and dried in a circulation dryer. 445 g (90% of theory) of 2,6-dichloro-3-fluoro-4-trifluoromethyl-phenylhydrazine of melting point 50° to 51° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][C:8](=[O:9])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].CCCCCC>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([CH2:22][O:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][C:8](=[O:9])[C:4]=2[CH:3]=1)=[O:24])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: O=C1COc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CO2
Yield: 98 %

Procedure:
3.00 g (20 mmol) XVIII, 3.96 g (40 mmol) K2CO3 and 5.54 ml (50 mmol) bromoacetic acid ethyl ester were heated under reflux for 72 h in 150 ml tetrahydrofuran. After filtration, the solvent was removed. Flash chromatography (200 g SiO2, n-hexane:ethyl acetate=2:1) produced 4.63 g (19.6 mmol, 98%) XIX.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.31 g, 2.6 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 0.18 g, 45%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][CH:13]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][CH:13]=2)=[CH:7][CH:8]=1)=[O:23]
Reactant: CSc1ccc(-c2csc(NC(C)=O)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Nc1nc(-c2ccc(S(C)=O)cc2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 132 %

Procedure:
N-{4-[4-(Methylthio)phenyl]-1,3-thiazol-2-yl}acetamide (2 g) was suspended in CH2Cl2 (20 ml), and then 3-chloroperoxybenzoic acid (1.44 g) was added portionwise to the suspension at 0° C. The reaction mixture was stirred at r.t. for 15 minutes. The precipitate was filtered in vacuo, and the solid was washed with 1N—Na2CO3, water and EtOH to give N-{4-[4-(methylsulfinyl)phenyl]-1,3-thiazol-2-yl}acetamide (2.80 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:6]=1[C:7]([NH:9][C:10]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:13])=[O:8].[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](O)=[O:42]>C(Cl)Cl>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[C:5]([O:4][CH2:3][CH2:2][NH:1][C:41]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)=[O:42])[CH:33]=1
Reactant: O=C(O)c1cccs1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCN)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCNC(=O)c2cccs2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 2-[2-(2-aminoethoxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (227 mg, 0.47 mmol), P-EPC resin (2.09 g, 1.78 mmol), and thiophene-2-carboxylic acid (144 mg, 1.12 mmol) in methylene chloride (15 mL) was shaken in a screw top vial overnight. The reaction was filtered and the solids were washed with 10% methanol in chloroform. The filtrate was concentrated to yield the desired product (265 mg, 0.45 mmol, 95%) as a greenish solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Br:1][C:2]1[CH:8]=[C:7]([I:18])[CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[NH2:4]
Reactant: CC(C)(C)c1cccc(Br)c1N
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(I)cc(Br)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
In a 50 mL round-bottom flask was added 2-bromo-6-tert-butylaniline [prepared by the method of Onitsuka, et. al. Organometallics, 25(5), 2006, pp 1270-1278] (1.18 g, 5.17 mmol) and sodium bicarbonate (0.782 g, 9.31 mmol) in water (5 ml). The mixture was cooled in an ice bath and iodine (1.444 g, 5.69 mmol) was added in several portions. The mixture was warmed to ambient temperature and stirred for 16 h. The mixture was treated with aqueous sodium thiosulfate, extracted by ethyl acetate, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel eluting with 5% ethyl acetate in hexane to give an oil (1.2 g, 65%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.[C:15](OC(=O)C)(=O)C.N1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:5]([CH2:4][C:1](=[O:3])[CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1cccc(F)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Cc1cccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
2-Carboxymethyl-6-fluoro-benzoic acid (11.16 g, 56.32 mmol) in acetic anhydride (65 mL, 690 mmol) was heated at 110° C. for 60 minutes. Pyridine (20 mL, 250 mmol) was added. Gas evolution was observed. The reaction mixture was refluxed overnight and rotovaped. The residue was dissolved in tetrahydrofuran (100 mL) and 4 M aq. NaOH (100 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with conc. HCl (aq). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine, dried over MgSO4 and rotavaped. 20 mL toluene was added and the mixture was rotovaped to give crude 2-Fluoro-6-(2-oxo-propyl)-benzoic acid (12.3 g, yield 55.7%, purity ca. 50%). The purity was estimated by 1H NMR and the crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][CH:27]([CH3:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:29]([CH2:28][CH:27]([CH3:33])[CH3:26])(=[O:31])=[O:30])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(N[C@H]2CCCNC2)n1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(Br)c(N[C@H]2CCCN(S(=O)(=O)CC(C)C)C2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A solution of (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (1.0 g, 3.3 mmol) from Scheme 1, step 1, Example 76 and diisopropylethylamine (1.6 ml, 6.6 mmol) in dichloromethane (15 ml) was cooled to 5° C. and treated with a solution of 2-methylpropane-1-sulfonyl chloride (0.52 g, 3.3 mmol) in dichloromethane (2 ml) similar to step 2. This was stirred at room temperature for 16 hours, washed with water, dried (MgSO4) and evaporated to give an oil. This was purified by silica gel chromatography (50-80% ethyl acetate/hexane) to give 1.0 g (65%) (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine. MS (ES+): 424
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=1)[NH:7][N:6](COCC[Si](C)(C)C)[CH2:5]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3c2NN(COCC[Si](C)(C)C)C3)(c2ccc(F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 55 °C
Yield: 85.6 %

Procedure:
Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (420 mg, 0.660 mmol) was dissolved in TBAF (1M in THF) (8.5 mL, 8.50 mmol). The flask was sealed and heated at 55° C. for 1.5 h. The reaction was cooled to room temperature and diluted with ether, washed with water then brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (30%-40% EtOAc/Hex) to give title compound (286 mg, 0.565 mmol, 86% yield) as a colorless oil. LC/MS (HPLC method 3): tR=3.78 min, 506.3(MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C.O.N>[C:20]([C@@H:24]1[CH2:25][CH2:26][C@H:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:4][N:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1nnc(CCc2cccnc2)c2ccccc12
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2nnc(CCc3cccnc3)c3ccccc23)CC1

Procedure:
Under N2-atmosphere, 500 mg (1.85 mmol) 1-chloro-4-[2-(pyridin-3-yl)ethyl]phthalazine and 1.25 g (8 mmol) of 4-tert.-butylcyclohexylamine (trans/cis mixture) are heated at 150° C. for 2.5 h. The reaction mixture is diluted with ethyl acetate, water and conc. NH3-solution (=1 ml), then the aqueous layer is separated off and extracted 2× with ethyl acetate. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; ethyl acetate to ethyl acetate/ethanol 10:1) yields the trans isomer followed by the cis isomer of the title compound. trans 1-(4-tert.-Butylcyclohexylamino)-4-[(2-(pyridin-3-yl)ethyl]phthalazine: m.p. 155-157° C.; 1H-NMR (DMSO-d6) 8.50 (s, 1H), 8.38 (d, 1H), 8.35 (d, 1H), 8.06 (d, 1H), 7.83 (m, 2H), 7.74 (d, 1H), 7.30 (m, 1H), 6.89 (d, HN), 4.08 (m, 1H), 3.38 (t, 2H), 3.10 (t, 2H), 2.12 (m, 2H), 1.81 (m, 2H), 1.35 (q, 2H), 1.14 (q, 2H), 1.07 (m, 1H), 0.88 (s, 9H); FAB-MS (M+H)+=389. cis 1-(4-tert.-Butylcyclohexylamino)-4-[(2-(pyridin-3-yl)ethyl]phthalazine: 1H-NMR (DMSO-d6) 8.48 (m, 2H), 8.38 (d, 1H), 8.08 (m, 1H), 7.84 (m, 2H), 7.73 (m, 1H), 7.29 (m, 1H), 6.49 (d, HN), 4.33 (sb, 1H), 3.39 (m, 2H), 3.10 (m, 2H), 2.18 (d, 2H), 1.6-1.4 (m, 6H), 1.06 (m, 1H), 0.87 (s, 9H); FAB-MS (M+H)+-=389.