Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].Br[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38].C(OCC)(=O)C.O>C(N(CC)CC)C.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>[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1cccc(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(CC#Cc2c(F)cccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
A mixture of 1.07 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 10 cm3 of triethylamine was stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 0.156 g of tetrakis(triphenylphosphine)palladium, 0.051 gof cuprous iodide, and 0.78 g of 1-bromo-2,6-difluorobenzene were added. The mixture was stirred for 3 hours 30 minutes at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 30 cm3 of ethyl acetate and 30 cm3 of water added. After stirring for 10 minutes, the mixture was separated by settling. After separating off the organic phase, the aqueous layer was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 50 g), elution was carried out with pure ethyl acetate, and first a fraction of 300 cm3 were collected, followed by 38-cm3 fractions. Fractions 6 to 16 were combined and concentrated as above. 0.55 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,6-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with a pale yellow color.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH:23]=1.CC1(C)[C@]23C4(ON4S(=O)(=[O:39])C2)C[C@H]1CC3>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]([C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C@@H:23]1[CH2:24][CH2:25][CH2:26][C@:22]1([OH:39])[C:27]([O:29][CH3:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=CCCC1
Reactant: CC1(C)[C@@H]2CC[C@@]13CS(=O)(=O)N1OC13C2
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(O)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
According to the procedure of Tet. Asymm., 13, 2002, 1555: To a solution of (R)-N-benzyl-N-α-methylbenzylamine (1.37 mL, 2 eq.) in THF (10 mL) at −78° C. was added n-butyllithium (2.4 M, 2.2 mL, 1.6 eq). The reaction was allowed to stir for 30 min at −78° C. and then methyl 1-cyclopentene-1-carboxylate (0.41 mL, 3.25 mmol, 1 eq) was added dropwise. The reaction was stirred for 3 h at −78° C. and then a solution of (1R)-(−)-(10-camphorsulfonyl)oxaziridine (1.49 g, 2 eq) in THF (12 mL) was added dropwise via cannula. The reaction was allowed to stir at room temperature overnight, and was then taken up in ethyl acetate, washed with NaHCO3 (1×), brine (2×), dried over Na2SO4, filtered and concentrated. Purification by silica chromatography eluting with a gradient of 10-15% ethyl acetate/hexanes afforded methyl (1R,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-hydroxycyclopentanecarboxylate as an off white solid (0.77 g, 69%). MS: 354.2 (M+H)+
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]([CH3:16])([CH3:15])[C:11](OC)=[O:12].[F:17][C:18]([S:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([F:20])[F:19]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:16][C:10]1([CH3:15])[NH:9][C:29](=[O:30])[N:28]([C:25]2[CH:24]=[CH:23][C:22]([S:21][C:18]([F:20])([F:17])[F:19])=[CH:27][CH:26]=2)[C:11]1=[O:12]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)cc2)C1=O
Temperature: 20 °C
Yield: 95.6 %

Procedure:
5.12 ml of triethylamine and 2.8 g of methyl α-aminoisobutyrate hydrochloride are added to a solution of 4 g of 4-trifluoromethylsulfanylphenyl isocyanate in 40 ml of toluene, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture thus obtained is refluxed for 24 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure and the residue obtained is taken up in ethyl ether and filtered. 5.3 g of 5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione are thus obtained, the characteristics of which product are as follows:
Reaction SMILES: C([NH:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 1.4 g of 4-(4-acetamidophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid and 14 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. Aftercooling to room temperature it is filtered and the filtrate acidified with glacial acetic acid to pH = 4. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid of the formula ##SPC12##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5](O)=[O:6].S(Cl)([Cl:21])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5]([Cl:21])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1N1CCCN(C)CC1
Reactant: O=S(Cl)Cl
Product: Cc1cc(C(=O)Cl)ccc1N1CCCN(C)CC1

Procedure:
Prepared analogously to Example 29a from 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid and thionyl chloride.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH3:6])[NH:12][CH:11]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: COc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2[nH]cc(C=O)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Add phosphorus oxychloride (1.1 eq.) with vigorous stirring to DMF (cooled in an ice bath). After the addition is complete, allow to stir in the ice bath for ˜10 minutes, then add a solution of 4-methoxy-1H-indole (5 g) in anhydrous DMF with vigorous stirring. Allow to stir at 0° C. After 1 hour, warm to room temperature. After 16 hours, carefully add 4 eq. of 2N NaOH with vigorous stirring. Heat to about 80° C. and then cool. Pour the reaction mixture into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry in a vacuum oven at room temperature to give the title compound. Acidify the filtrate and extract with EtOAc. Combine the organic layers and wash with 50% brine. Collect the organic layer, dry (MgSO4) filter, and remove the solvent to give the title compound as a light purple solid. Total yield of the title compound is 5.44 g: MS (ES+): m/z 175 (M+H)+, 160 (M-CH3)+; (ES−): m/z 174 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[N:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([NH:24][C:15]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:6]=2)=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1ccc(Cl)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 350.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19](Br)[CH2:20][CH3:21])[N:18]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][CH2:21][CH:25]4[CH2:26][CH2:27][CH2:28][NH:23][CH2:24]4)[N:18]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CCC(Br)n1ncc(-c2ccc(-c3ccc(Cl)cc3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(-c2ccc(-c3cnn(CCCC4CCCNC4)n3)cc2)cc1
Yield: 131.3 %

Procedure:
41-[3-[4-(p-chlorophenyl)-5-phenyl-(-[1,2,3]triazol-2-yl)]-3-bromopropane (26 mg, 0.07 mmol) and piperidine (9 mg, 0.10 mmol) were refluxed in ethanol for 1 h in presence of dry sodium carbonate (11 mg, 0.10 mmol). The reaction mixture was then filtrated. The solid was washed with CH2Cl2. The combined filtrates was evaporated in vacuo. The resulting oil was then purified by chromatography on silica gel eluting with EtOAc to afford 1-[3-[4-(p-chlorophenyl)-5-phenyl-(-[1,2,3]triazol-2-yl)propyl]-piperidine (35 mg, 75% yield); 1H NMR (200 MHz, CDCl3, 25° C.) δ=7.53-7.46 (4H, m), 7.39-7.31 (5H, m), 4.52 (2H, t, 3J=7.1 Hz), 2.46-2.39 (6H, m), 2.23 (2H, qt, 3J=7.2 Hz), 1.58 (4H, qt, 3J=5.5 Hz), 1.42 (2H, qt, 3J=5.5 Hz) ppm. ES-MS: m/z=382 (5), 381 (4), 380 (14) [M+●]; 98 (100) [M-283]; 84 (30) [M-297].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.CCN(C(C)C)C(C)C.[Cl-].[CH:28]1([O:34][C:35]([C:37]2[N:38]=[C:39]([CH:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)[S:40][CH:41]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([CH2:12][C:13]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:35]([O:34][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:36])[N:38]=3)[CH2:47][CH2:46]2)=[O:15])[N:4]=1
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (348 mg, 65%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][C:29]=3[C:5]=2[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Yield: 15.2 %

Procedure:
Preparation of the title compound was carried out according to General Method 1 by using 4-chlorophenylhydrazine hydrochloride (5 g, 27.9 mmol), ethyl bromoacetate (4.6 g, 27.9 mmol), triethylamine (11.6 mL, 83.2 mmol) and N-methyl-4-piperidone hydrochloride (5.2 g, 34.9 mmol) in ethanol (50 ml) to obtain 1.3 g of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with dichloromethane-hexane gradient.
Reaction SMILES: Br.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4].C(N(CC)CC)C.[C:24]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH:29]([C:34](=O)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28]1)(=[O:26])[CH3:25].N(C1N=C(C2C=CC=CC=2)SC=1)C(N)=N>CC(C)=O>[C:24]([N:27]1[CH2:28][C:29]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:4][C:3]([NH:2][C:6]3[S:7][CH:8]=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[N:5][C:30]=2[CH2:31][CH2:32]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC(=O)C(C(=O)c2ccccc2)C1
Reactant: N=C(N)Nc1nc(-c2ccccc2)cs1
Agent: Br
Agent: N=C(N)Nc1csc(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(Nc3nc(-c4ccccc4)cs3)nc(-c3ccccc3)c2C1
Yield: 26.6 %

Procedure:
To 2-guanidino-4-phenylthiazole hydrobromide (13.14 g, 0.044 mol) was added acetone (240 mL), with stirring. Triethylamine (4.45 g, 6.3 mL, 0.044 mol) was added. The resulting solution was heterogeneous. N-Acetyl-3-benzoyl-4-piperidone (7.18 g, 0.029 mol) was dissolved in acetone (30 mL), with gentle warming, then added to the guanidino phenylthiazole solution. The reaction mixture was heated at reflux for three days. The solid which had precipitated was filtered in a sintered glass funnel, and washed with water to remove triethylamine hydrobromide. The remaining solid, composed of the desired product along with a small amount of the excess starting guanidino phenylthiazole, was recrystallized from methanol to give 3.29 g (7.7 mmol) of the title compound as a tan solid; mp 130°-132° C. A second crop precipitated from the mother liquor and was recrystallized from methanol to give an additional 2.7 g (6.3 mmol). The combined yield was 48%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[N:12][CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2)cn1
Reaction time: 240 h
Yield: 17.2 %

Procedure:
2-[(4-Fluorophenyl)sulfonyl]-5-[(E)-2-(4-fluorophenyl)vinyl]pyridine (Example 37, 0.11 g, 0.308 mmol) and palladium (10% wt. on activated carbon, 32 mg) were suspended in ethyl acetate (5 mL) and acetic acid (5 mL) and shaken in a Parr apparatus at 50 psi hydrogen for 2 days. The catalyst was removed by filtration, fresh catalyst (80 mg) added and shaking at 50 psi hydrogen continued for 10 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The aqueous phase was extracted with further portions of ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (19 mg, 17%). δH (500 MHz, d6 DMSO): 8.52 (1H, s), 8.10 (1H, d, J=8.0 Hz), 8.02–7.99 (2H, m), 7.95 (1H, dd, J=1.9, 8.0 Hz), 7.46 (2H, t, J=8.8 Hz), 7.21 (2H, dd, J=5.7, 8.4 Hz), 7.05 (2H, t, J=8.9 Hz), 2.97–2.94 (2H, m), 2.89–2.85 (2H, m); m/z (ES+) 360 [MH+].
Reaction SMILES: C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]=C)[N:10]=[C:9]([O:19][CH2:20]C)[CH:8]=1)(C)(C)C.F[C:24](F)(F)[C:25](O)=O>>[CH2:24]([CH:14]([NH:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([O:19][CH3:20])[N:10]=1)[C:6]([OH:5])=[O:22])[CH2:15][CH:16]=[CH2:17])[CH3:25]
Reactant: C=CCCCNc1cc(C(=O)OC(C)(C)C)cc(OCC)n1
Reactant: O=C(O)C(F)(F)F
Product: C=CCC(CC)Nc1cc(C(=O)O)cc(OC)n1

Procedure:
The title compound is prepared by stirring 2-ethoxy-6-pent-4-enylamino-isonicotinic acid tert-butyl ester 18 h in neat trifluoroacetic acid. Evaporation of the TFA gives the title compound that is used in the next step without purification.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][S:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2scc(-c3ccccc3)c12
Product: Clc1ncnc2scc(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one (294.6 g, 1.29 mol) was added in portions to stirred phosphoryl chloride (1000 ml), then the stirred suspension was warmed gently to reflux temperature, heated under reflux for 4 hours, and allowed to stand at ambient temperature for 18 hours. The resulting dark solution was removed by decantation from a solid residue and concentrated in vacuo to give a gummy solid. The two solids were combined and added to crushed ice (1000 ml). The product was extracted into dichloromethane (3×500 ml), then the combined extracts were washed with water (2×300 ml) and saturated aqueous sodium hydrogen carbonate solution (500 ml) and dried and decolourised (MgSO4+charcoal). The solvent was removed in vacuo to give 4-Chloro-5-phenyl-thieno[2,3-d]pyrimidine as a yellow/orange solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[C:57]([SiH:61]([CH3:63])[CH3:62])([CH3:60])([CH3:59])[CH3:58]>ClC(Cl)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si:61]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:63])[CH3:62])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C[SiH](C)C(C)(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.82 g, 5.76 mmol) in dichloroethane (100 mL) was added triethylamine (1.285 mL, 9.22 mmol), tert-butyldimethylsilane (1.912 mL, 11.52 mmol), and palladium(II) acetate (0.647 g, 2.88 mmol). The mixture was flushed with N2 and was heated to 60° C. After 2 h, the reaction was cooled to rt, was filtered through a pad of celite and silica gel to remove the solids which were washed with 25% EtOAc in hexanes. The filtrate was concentrated under reduced pressure and was treated with 20 mL of acetic acid, 10 mL of THF and 3 mL of water. After stirring for 1 h the solids that formed were collected by filtration and were washed with water to give (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.62 g, 5.27 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=8.28 Hz, 2H), 7.21 (d, J=8.28 Hz, 2H), 5.30 (dd, J=6.15, 1.63 Hz, 1H), 4.75 (d, J=1.76 Hz, 1H), 4.62 (s, 1H), 3.92 (s, 4H), 3.08 (td, J=10.92, 4.27 Hz, 1H), 2.35-2.22 (m, 2H), 2.17-2.06 (m, 1H), 2.02-1.84 (m, 2H), 1.71 (s, 3H), 1.01 (s, 6H), 0.99 (br. s., 3H), 0.98 (s, 9H), 0.94 (s, 6H), 1.78-0.90 (m, 16H), 0.32-0.28 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:30])[N:10]2[CH:13]([CH3:29])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:30])[CH3:29])[CH2:16][CH2:17]1
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Reaction time: 2 h
Yield: 105.4 %

Procedure:
A solution of tert-butyl {1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}carbamate (Intermediate 222, 200 mg, 0.48 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL). After 2 hours, the reaction was concentrated to dryness. The residue was partitioned between 15% methanol/chloroform. The aqueous phase was re-extracted 3× with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness giving 160 mg (100%) of the crude product as an oil.