Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:34]([C:35](=O)[C:36]#[CH:37])=[C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][N:24]3[N:23]=2)=[CH:18][CH:17]=1>C(O)C.O>[CH:2]1([NH:7][C:8]2[N:10]=[C:35]([C:34]3[C:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)=[N:23][N:24]4[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=34)[CH:36]=[CH:37][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5 mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M in ethanol, 14 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. To this mixture was added 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin -3-yl]-2-propyn-1-one (3.44 g, 10.4 mmol) portionwise The reaction mixture was stirred at 0° C. for 30 minutes, followed by room temperature for 15 hours. The reaction mixture was diluted with water (400 mL). The solid precipitate was collected on a filter to provide N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (4.48 g, 98%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t, 2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34(m, 1H), 2.15–2.06 (m, 2 H), 1.84–1.52 (m, 6H); 19F NMR (CDCl3): δ−62.70, −112.25 MS m/z 442 (M+1); mp 155–156° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CCCCCCCCCCCCCCCCCCSCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCSCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C

Procedure:
rac-1,2-Epoxy-3-octadecylthiopropane (2.0 g, 5.83 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1-[2'-hydroxy-3'-octadecylthiopropyl]-cytosine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:28])=[CH:21][CH:20]=1)=[O:25]
Reactant: COC(=O)CCc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 48.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 4.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.5 g of methyl 3-[4-(2-oxopropoxy)phenyl]propionate (prepared as described in Preparation 5), 100 ml of benzene, 100 ml of absolute methanol and 2.6 g of sodium cyanoborohydride, 2.8 g of the title compound were obtained as crystals, melting at 65°-73° C.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[O:36])#[N:31]>[Cl-].[NH4+].C(OCC)(=O)C>[OH:36][CH:35]([C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1)[C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[C:30]#[N:31]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)[Si](OCc1ccc(Br)cc1)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
Stir a solution of (4-bromo-benzyloxy)-triisopropyl-silane (72 g, 209.7 mmol) and tetrahydrofuran (500 mL) at −78° C. Add a 1.6 M solution of n-butyllithium in hexanes (143 mL) over 10 min. After addition, allow the reaction mixture to reach −20° C. and stir for 5 minutes. Cool the reaction mixture to −78° C. In another flask, stir a solution of 3-cyanobenzaldehyde (25 g, 190.6 mmol) and tetrahydrofuran (250 mL) at −78° C. Add the lithium anion solution to the aldehyde solution via large canula at a rate such that the internal aldehyde temperature does not rise above −50° C. After addition is complete, stir the reaction mixture 18 hours at room temperature. Dilute the reaction mixture with aqueous saturated ammonium chloride (500 mL) and ethyl acetate (200 mL). Separate the layers, and extract the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue via silica gel chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to afford the title compound (56.1 g, 75%) as a colorless oil. LCMS (m/z) 396 M+1.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=C(CCO)C=C[CH:26]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[CH:26]=[C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH:3]=[CH:2][CH:22]=1
Reactant: COc1cccc(CCO)c1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1cccc(CCOc2cccc3[nH]c(C(=O)O)cc23)c1

Procedure:
4-[2-(3-Methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid (16k) is synthesized analogous to 16a from 2-(3-methoxy-phenyl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Na+].[I-].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][C@@H:18]4[CH2:24][CH2:25][N:49]([CH:46]5[CH2:48][CH2:47]5)[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H]3CCN(C4CC4)C3=O)c2)cn1
Temperature: 120 °C
Yield: 42 %

Procedure:
To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added NaI (62 mg, 0.41 mmol) and cyclopropylamine (56 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the racemic product (91 mg, 42%). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-cyclopropyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ column eluting with methanol at a flow rate of 60 mL/min. 91 mg of racemic material was separated in 1 injection of 5 mL at 18 mg/ml in methanol to afford the product which eluted before its enantiomer (27 mg, 12%). 1H NMR δ (300 MHz, CDCl3) 0.66-0.91 (m, 4H), 2.14 (sextet, 1H), 2.35 (quintet, 2H), 2.48-2.62 (m, 4H), 2.66-2.78 (m, 1H), 3.27-3.49 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.92 (t, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.57 (s, 1H), 9.51 (s, 1H); m/z 529 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22](O)[CH3:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(=[O:59])[NH:53][C:52](=[O:54])[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]([N:53]2[C:49](=[O:59])[C:50]3[C:51](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:52]2=[O:54])[CH3:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:14]=[CH:13][CH:12]=2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethanol (0.08980 g, 0.2546 mmol) in tetrahydrofuran (2.546 mL, 0.2546 mmol) were added triphenylphosphine (0.2003 g, 0.7637 mmol), phthalimide (0.1124 g, 0.7637 mmol), and diisopropyl azodicarboxylate (0.1504 mL, 0.7637 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 20 min and 50% isocratic of EtOAc for 10 min as eluent to give 2-(1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethyl)-isoindoline-1,3-dione as a yellow solid: LC-MS (ESI) m/z 482.0 [M+H]+.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@H:44]1[CH2:48][C@@H:47]([CH2:49][S:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:46]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:45]1.C(OCC)(=O)C>C(#N)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:18]([S:43][C@H:44]3[CH2:48][C@@H:47]([CH2:49][S:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:46]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=4)=[O:58])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSc1ccccc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4ccccc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 5 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.24 g, 3.78 mmol) in acetonitrile (70 ml), DIPA (0.9 ml, 5.16 mmol) was added under cooling with ice, and then a solution of (3S,5S)-3-mercapto-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidine (1.39 g, 3.42 mmol) in acetonitrile (15 ml) was dropwise added thereto. The reaction solution was stirred at 5° C. overnight, and ethyl acetate (300 ml) was added to the reaction solution. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate), to give p-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(3S,5S)-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1.55 g, yield: 60%).
Reaction SMILES: O[CH:2]1C2C(=CC=CC=2)C(=O)[N:3]1CC1SC=CC=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([S:28][CH2:29][C:30]([NH:32][C:33]2S[CH:35]=[CH:36][N:37]=2)=[O:31])[N:20]1[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1>>[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([S:28][CH2:29][C:30]([NH:32][C:33]2[CH:2]=[N:3][CH:35]=[CH:36][N:37]=2)=[O:31])[N:20]1[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1nccs1
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Product: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1cnccn1

Procedure:
Compound 31 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 14 and illustrated in Scheme 1b. 1H NMR (300 MHz, DMSO): δ 10.65 (s, 1H), 9.12 (s, 1H), 8.34 (s, 2H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H), 7.43 (m, 2H), 7.09 (m, 1H), 6.97 (m, 1H), 5.77 (s, 1H), 5.13 (d, J=15 Hz, 1H), 4.66 (d, J=16 Hz, 1H), 3.10 (d, J=15 Hz, 1H), 2.98 (d, J=15 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][NH:23][CH3:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([N:23]([O:22][CH3:21])[CH3:24])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC
Yield: 81 %

Procedure:
2-Allyloxycarbonylamino-succinic acid 4-tert-butyl ester, 100, (43.4 g, 0.159 mol) is dissolved in CH2Cl2(900 mL). To this solution O,N-dimethyl-hydroxylamine hydrochloride (18.6 g, 0.191 mol), 4-Methyl-morpholine (21.0 mL, 19.3 g, 0.191 mol), and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.6 g, 0.191 mol) are added. After the consumption of the starting material, the solution is washed with 1.0 N HCl (2×400 mL) and brine (1×250 mL). The organic layer is concentrated in vacuo and the residue purified over silica (hexanes/ethyl acetate 65:35) to afford 40.8 g (81% yield) of the desired product as a clear oil. 1H-NMR, (300 MHz, CDCl3): δ 1.43 (s, 9H), 2.50–2.74 (m, 2H), 3.22 (s, 3H), 3.79 (s, 3H), 4.55–4.57 (d, J=4.8, 2H), 4.97–5.04 (m, 1H), 5.17–5.32 (m, 2H), 5.67–5.70 (d, J=9.0, 1H), 5.83–5.94 (m, 1H); 13C-NMR (75.5 MHz, CDCl3): δ 28.20, 32.58, 38.48, 61.83, 65.93, 81.53, 117.85, 132.88, 155.84, 169.46, 171.83; MS (ESI): m/e=317.11 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCCCCC.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[CH3:9])=[C:4]([Sn:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: C[Sn](C)(C)Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1[Sn](C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-chloro N-pivaloylaniline* (2.11 g, 10 mmol) in 30 ml of dry THF was cooled in an ice bath under an atmosphere of nitrogen. Then an hexane solution of 1.6M of n-Buli (15.625 ml, 25 mmol) was added dropwise. After stirring at 0° C. for 2.5 h, trimethyltin chloride (2.19 g, 11 mmol) dissolved in dry THF (8 ml) was added within 20 min at 0° C. The reaction was then stirred for 2 h at 0° C. and for 16 h at room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (di-isopropylether: petroleum ether 40°/70°=10:23) to yield 4-chloro-2-trimethylstannyl-N-pivaloylaniline as a white solid 3.1 g; 82.9%; m.p. 169°-172° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14](C=O)[CH3:15].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>O>[CH3:13][N:14]([CH3:15])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 4-nitro-benzoic acid (20 g, 0.1196 mol) in DMF (300 mL) N,N-dimethylamine hydrochloride (11.7 g, 0.1436 mol), HOBt (20.9 g, 0.1554 mol), EDC.HCl (34.3 g, 0.1794 mol) and DIPEA (30.91 g, 0.2392 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×500 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [23.0 g, 99%]; LC-MS (ESI): Calculated mass: 194.1; Observed mass: 195.1 [M+H]+ (RT: 1.70 min).
Reaction SMILES: [N+](=C[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5])=[N-].C.C[OH:20]>C([O-])(=O)C1C=CC=CC=1.[Ag+]>[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4]([OH:5])=[O:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Reactant: CO
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O

Procedure:
tert-Butyl (2S)-2-(diazoacetyl)-1-pyrrolidinecarboxylate (16 g, 46 mmol) was dissolved in 50 mL anhydrous methanol. Silver benzoate (0.1 mL of a 1 g solution in 12 mL TEA) was added. After 14 at room temperature, Norit was added and the mixture was concentrated in vacuo. Purifcation on SiO2 (hexanes:EtOAc 6:1 then 4:1) provided the methyl ester as a clear oil (8.35 g, 34.3 mmol, 69% from Boc-proline): 1H NMR (400 MHz, CDCl3) δ 4.12 (bs, 1H), 3.65 (s, 3H), 3.34 (m, 2H), 2.85 (m, 1H), 2.29 (dd, J=9.6, 15.2 Hz, 1H), 2.1 (m, 1H), 1.8–1.6 (m, 3H), 1.44 (s, 9H) ppm. ESMS m/z 244 (MH)+, 144 (MH−C5H8O2)+.
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]=3[CH:20]=[CH:21][CH:22]=2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([SH:24])[C:13]=3[CH:20]=[CH:21][CH:22]=2
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: COS(=O)(=O)OC
Product: CSc1ccc2c3c(cccc13)C(S)=N2

Procedure:
Chlorosulfonation of benz(cd)indol-2-(1H-one yields the 6-sulfonylchloride derivative, which upon treatment with zinc dust in acetic acid-hydrochloric acid solution, yields 6-mercaptobenz(cd)indol-2-(1H)-one. Treatment with dimethyl sulfate in alkaline solution leads to 6-methylthiobenz(cd)indol-2-(1H)-one, which on heating with P2S5 in pyridine yields 6-methylthiobenz(CD)indol-2-thiol. The reaction of the latter compound with molar equivalents of 3-(4-pyridinyl)propanamine and mercuric acetate in ethanol, under the conditions of Example 55, leads to the title compound.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH3:18])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:4][CH3:1])=[C:12]([CH2:17][CH3:18])[CH:11]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OC
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Potassium carbonate (3.9 g, 28.3 mmol) and methyl iodide (0.59 mL, 9.43 mmol) were added to a solution of 4-Bromo-2-ethyl-phenol (1.9 g, 9.43 mmol, from step 1 of Example A(22)) dissolved in DMF (10 mL). The mixture was stirred for 16 h under N2 and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a yellow oil. The oil was purifed by silica gel chromatography to give the title compound as a clear oil (1.37 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[I:13]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Cl)c(I)cc1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 1-chloro-2-iodo-5-methoxy-4-nitrobenzene (113 g, 0.361 mol) in acetic acid (1 L) and water (50 mL) at 50° C., Fe (50.5 g, 0.903 mol) was added and the resulting mixture was stirred at 50° C. for 2 h. The mixture was allowed to cool to room temperature and then poured into ice-water. The precipitate was collected by filtration and rinsed with water. This crude product was dissolved with ethyl acetate (1 L) and filtered. The filtrate was washed with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (87 g, 85% yield).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C@H:7]1[CH2:12][C@H:11]2[C@:9]([CH3:13])([CH2:10]2)[C:8]1([CH3:15])[CH3:14])/[CH2:3][OH:4].[CH3:16][Mg]Cl.O1CCCC1.BrCBr.C([Mg]Cl)(C)(C)C>>[CH3:1][C:2]1([CH2:3][OH:4])[CH2:16][CH:5]1[CH2:6][C@H:7]1[CH2:12][C@H:11]2[C@:9]([CH3:13])([CH2:10]2)[C:8]1([CH3:15])[CH3:14]
Reactant: C/C(=C\C[C@H]1C[C@@H]2C[C@]2(C)C1(C)C)CO
Reactant: C[Mg]Cl
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: BrCBr
Product: CC1(CO)CC1C[C@H]1C[C@@H]2C[C@]2(C)C1(C)C
Temperature: 25 °C

Procedure:
System B: (E)-2-methyl-4-((1S,3S,5R)-1,2,2-trimethylbicyclo-[3.1.0]hexan-3-yl)but-2-en-1-ol (5 g, 24 mmol) (F. Schröder, WO 2006066436, priority 20.12.2005 to Givaudan) is added undercooling and stirring to methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol) under nitrogen. Dibromomethane and tert-butyl magnesium chloride are added at a temperature of 10°-20° C. The dibromomethane and tert-butyl magnesium chloride are each added in 3 portions, one portion of dibromomethane (4.2 g, 24 mmol) followed by a portion of tert-butyl-magnesium chloride (12 ml, 24 mmol). After the addition of each pair of portions (72 mmol) the mixture is stirred for an appropriate time at room temperature. When complete or nearly complete conversion is reached, as checked by GC, the mixture is quenched by addition of conc. NH4Cl. Tert-Butyl methyl ether extraction, washing of the organic phase with H2O until pH 7, drying over MgSO4 and concentration gives 16.6 g of an an oily residue, which is bulb-to bulb-distilled at 120° C./0.07 Ton giving 4.7 g (89%) of Javanol (dr=1:1), whose analytical data are consistent with the ones described for this compound in the literature (J. A. Bajgrowicz, G. Frater, EP 801049, priority 9.4.1997 to Givaudan-Roure).