Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].C1C=CC=CC=1>O>[CH2:24]1[O:25][C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])([CH3:1])[O:10][CH2:23]1
Reactant: OCCO
Reactant: C=CCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCCCCCC1(C)OCCO1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution containing 119.0 g of non-8-en-2-one, (prepared in Example 22 B-3), 1.2 g p-toluenesulfonic acid monohydrate, 63.1 g of ethylene glycol and 420 ml anhydrous benzene was prepared and refluxed for about 15 to 17 hr. Water which formed was collected in a Dean-Stark trap. The solution was cooled to room temperature and 250 ml of 5% aqueous sodium bicarbonate solution was added thereto. The benzene layer was separated and dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was distilled to yield 116.8 g of title compound having the following physical characteristics:
Reaction SMILES: CS(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:28](=[O:29])[C@H:27]([NH2:30])[CH2:26][C:25]3[CH:24]=[CH:23][C:22]4[NH:21][N:20]=[CH:19][C:18]=4[C:17]=3[CH2:16]2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].[C:31](O)(=[O:33])C.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][C:42]2=[O:51])[CH2:37][CH2:36]1>>[C:6]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:28](=[O:29])[C@H:27]([NH:30][C:31]([N:35]3[CH2:36][CH2:37][CH:38]([N:41]4[CH2:50][C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[NH:43][C:42]4=[O:51])[CH2:39][CH2:40]3)=[O:33])[CH2:26][C:25]3[CH:24]=[CH:23][C:22]4[NH:21][N:20]=[CH:19][C:18]=4[C:17]=3[CH2:16]2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](N)C2=O)CC1
Reactant: CC(=O)O
Agent: CS(=O)(=O)O
Product: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C2=O)CC1
Yield: 28 %

Procedure:
(R)-9-(1-acetylpiperidin-4-yl)-7-amino-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one methanesulfonate (42 mg, 0.08 mmol) and 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one acetate (30 mg, 0.10 mmol) were reacted in a manner analogous to the preparation of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide. C18 preparatory HPLC afforded the title compound as white solid in 28% yield. High resolution MS m/e (M+H)+=599.3085.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][CH:41]=[C:40]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52].Cl[Si](C)(C)C>CCOCC.CO>[ClH:36].[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][C:40]2[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([Cl:36])[CH:38]=3)[NH:42][CH:41]=2)[CH2:8][CH2:7]1.[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:51](=[O:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][C:40]2[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([Cl:36])[CH:38]=3)[NH:42][CH:41]=2)[CH2:4][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(O)CCCCCc1c[nH]c2ccc(Cl)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCCCc2c[nH]c3ccc(Cl)cc23)CC1
Product: Cl
Reaction time: 48 h

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (152 mg, 0.65 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (207.5 mg, 0.75 mmol.) was added to a solution of 6-(5-chloro-1H-indol-3-yl)hexanoic acid (174 mg, 0.65 mmol.) in abs. methanol (5 ml), and stirring was carried out for 2 d at RT. For working up, the mixture was concentrated, water (15 ml) was added to the residue, the pH was adjusted to 11 with 5M NaOH and extraction was carried out with EE (4×15 ml). The combined extracts were washed with 1M NaOH (2×2 ml), dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target product, which was separated by flash chromatography on silica gel (35 g) and purified (eluant: 600 ml of methanol/EE 1:1). The resulting non-polar diastereoisomer (110 mg, 0.23 mmol.) was dissolved in 2-butanone (5 ml), and chlorotrimethylsilane (44 μl, 0.35 mmol.) was added thereto. There immediately formed a white precipitate, which after 15 min. was deposited in a tacky manner on the wall of the flask. The solvent was reduced to about 0.5 ml in vacuo, ether (2 ml) was added to the residue, and vigorous stirring was carried out for 1 h. The solid that formed was filtered off with suction, washed with ether (2×1 ml) and dried in vacuo. The hydrochloride of the non-polar diastereoisomer of 6-(5-chloro-1H-indol-3-yl)hexanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was thus obtained in the form of a slightly hygroscopic solid in a yield of 124 mg (m.p. 135–145° C.).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:37])[C:18]4[C:23]([C:24]=3[C:25]3[S:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:28][CH:29]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11](I)[C:4]=12.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([OH:45])[CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:37])[C:18]4[C:23]([C:24]=3[C:25]3[S:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:28][CH:29]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([C:41]3[CH:42]=[C:43]([OH:45])[CH:44]=[C:39]([F:38])[CH:40]=3)[C:4]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)s1)n1nc(I)c2c(N)ncnc21
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 71.8 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-isochromen-1-one hydrochloride (Intermediate D9, 100 mg, 0.154 mmol), 3-fluoro-5-hydroxyphenylboronic acid (48.1 mg, 0.308 mmol), S-Phos-Pd-G2 (11.10 mg, 0.015 mmol) and K3PO4 (151 mg, 0.462 mmol) were reacted in THF (1.2 ml) and water (0.3 ml) under argon at 80° C. under mw irradiation for 30 min The reaction was quenched by the addition of 1M HClaqueous (2 ml) and the mixture purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give (prior to drying a small amount of 1M HCl aqueous was added) the title compound (70 mg, 71.7% yield) as yellowish solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.I[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+].C(OC)(C)(C)C>CN(C)C=O>[CH3:18][C:10]([CH3:19])([CH2:9][CH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([O:1][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH2:3]1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC[C@H]1CCC[C@@H](O)C1
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
365 mg of tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate are, together with 850 mg of 4-iodomethyl-5-methyl-2-(4 methylphenyl)oxazole, dissolved in 5 ml of dimethylformamide, and 110 mg of sodium hydride (60% strength in paraffin) are added. After 1 hour of stirring at room temperature, 100 ml of methyl tert-butyl ether are added and the reaction mixture is washed three times with water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 330 mg of tert-butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyrate as a white solid. C28H41NO4 (455.64), MS(ESI): 456 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[C:11]([OH:19])[CH:10]=1)=[O:7])([OH:3])=[O:2].[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CO>[CH2:20]([NH:26][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][C:11]=1[OH:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O
Reactant: CCCCCCN
Solvent: CO
Product: CCCCCCNC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O

Procedure:
Methyl 4-(3-carboxy-propionylamino)-2-hydroxybenzoate from Example 2 (1 g) is dissolved in 15 mL of methanol. n-Hexylamine (5 mL) is added to this solution, and the reaction mixture is brought to mild reflux for 2 days. Solvents are removed under vacuum and residue acidified using 1 N HCl. N-n-hexyl 4-(3-carboxy-propionylamino)-2-hydroxybenzamide precipitate is collected, washed with water, and dried.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])(=[O:30])[CH3:29]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and acetic anhydride, to give the desired product as a light yellow solid (43%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].Cl.[CH3:32][C@@H:33]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C@H:34]([NH:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:35](ON1C(=O)CCC1=O)=[O:36].C(N(CC)CC)C>CN(C)C=O>[NH:45]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:34]([C:35]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:36])[C@@H:33]([CH3:32])[O:56][C:57]([CH3:59])([CH3:60])[CH3:58]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(N)=O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
9.3 g of H-Gln-Asn-Phe-OCH3 hydrochloride and 11.9 g of Z-Thr(tBu)-OSU are dissolved in 150 ml of dimethylformamide to form a clear solution. 2.85 ml of triethylamine in 10 ml of dimethylformamide are added and the batch is stirred for 21 hours at room temperature. The batch is then concentrated under reduced pressure and taken up in much ethylacetate+chloroform (9:1), and extracted with 2 × 200 ml of 5% citric acid and 1 × 100 ml of water. The insoluble precipitate is then filtered off, the filtrate extracted with 2 × 200 ml of 2N-sodium carbonate solution and 3 × 100 ml of water, dried over sodium sulfate, and evaporated. The residue is recrystallized, together with the filter residue mentioned above, from dimethylformamide+ether (1:1). Melting point, 237°- 241°C (decomp.); [α]20D = + 8° (c = 1% in dimethylformamide).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:26][OH:27].Cl>O>[CH3:1][C:2]([CH3:20])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH2:4])[CH:3]=[N:26][OH:27]
Reactant: CCCCCCC1CC=CCCC=CCC(C)(C)C=N1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCC(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 200.5 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 113 g (0.41 mol) of 3,3-dimethyl-12-hexyl-1-aza-1,5,9-cyclododecatriene, 33 g (0.202 mol) of hydroxylamine sulfate, 50 g of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 125 g (0.405 mol) of 2,2-dimethyl-11-n-hexyl-11-amino-undeca-4,8-dienal oxime; yield 99% of theory.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1.[H-].[Na+].CN(C)C=O.CS([C:41]1[S:42][C:43]2[C:48]([N:49]=1)=[CH:47][CH:46]=[CH:45][N:44]=2)(=O)=O>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][C:41]3[S:42][C:43]4[C:48]([N:49]=3)=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)c1nc2cccnc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nc5cccnc5s4)CC3)nc3ccccc32)cc1
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred mixture of 5.3 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol dihydrochloride, 2.8 parts of a sodium hydride dispersion 50% and 90 parts of N,N-dimethylformamide were added 2.55 parts of 2-(methylsulfonyl)thiazolo[5,4-b]pyridine. The whole was stirred for 2 hours. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.9 parts (15%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(thiazolo[5,4-b]pyridin-2-yl)oxy]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 151.0° C. (compound 107).
Reaction SMILES: O.O.Cl[Sn]Cl.[Cl:6][C:7]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:8]=1[C:9]([N:11]1[CH2:17][CH2:16][CH:15]=[CH:14][C:13]2[S:18][CH:19]=[CH:20][C:12]1=2)=[O:10]>C(O)C>[Cl:6][C:7]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:8]=1[C:9]([N:11]1[CH2:17][CH2:16][CH:15]=[CH:14][C:13]2[S:18][CH:19]=[CH:20][C:12]1=2)=[O:10]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCC=Cc2sccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCC=Cc3sccc32)c(Cl)c1
Temperature: 75 °C

Procedure:
To a solution of 2.36 g of SnCl2.2H2O in 13 ml of ethanol is added 0.70 g of 4-(2-chloro-4-nitrobenzoyl)-5,6-dihydro-4H-thieno[3,2-b]azepine. The mixture is heated at 75° C. for one hour, cooled to room temperature and concentrated under vacuum to 10 ml. The mixture is chilled in an ice bath and 1M NaHCO3 added slowly. The mixture is extracted with 100 ml ethyl acetate and then with 80 ml of ethyl acetate. The extracts are combined, washed with brine and dried (Na2SO4). The extract is passed through a thin pad of hydrous magnesium silicate and the pad washed with ethyl acetate. The filtrate is concentrated to give a solid which is crystallized from ethyl acetate to give white crystals, m.p. 192°-200° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH2:35])=[CH:33][C:28]=2[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[Cl:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50]([Cl:64])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58](O)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]>ClCCl>[Cl:64][C:50]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:45])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58]([NH:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]3[O:25][CH2:26][CH2:27][C:28]=3[CH:33]=2)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]
Reactant: NCc1ccc2c(c1)CCO2
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)CCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 5.3 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (76.4 mg, 0.51 mmol), 2,3-dihydrobenzofuran-5-ylmethanamine (165.5 mg, 1.28 mmol) and diisopropylethylamine (12 mg, 0.12 mmol) was added to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) in dichloromethane (3 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a brown solid (11 mg, 5% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.28 (1H, m), 8.99 (2H, m), 8.46 (1H, s), 7.14 (1H, m), 7.00 (1H, m), 6.69 (1H, m), 4.48 (2H, m), 4.30 (2H, m), 3.15 (2H, m). MS m/z: 480.11, 482.11 [M+H]+.
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:11]([F:16])[CH2:10]1.[C:20]([OH:23])(=[O:22])[CH3:21]>>[Cl:3][C:4]1([Cl:1])[CH:17]([O:22][C:20](=[O:23])[CH3:21])[N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:11]([F:16])[CH2:10]2)[C:7](=[O:18])[NH:6][C:5]1=[O:19]
Reactant: ClCl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](F)[C@@H](CO)O2)cc1Cl
Reactant: CC(=O)O
Product: CC(=O)OC1N([C@H]2C[C@H](F)[C@@H](CO)O2)C(=O)NC(=O)C1(Cl)Cl
Reaction time: 0.5 h

Procedure:
Chlorine gas was bubbled slowly into a suspension of 5-chloro-3′-fluoro-2′,3′-dideoxyuridine (75 mg, 0.28 mmol) in glacial acetic acid (5 ml) at 25° C. with stirring until the light yellow-green color of the resulting solution persisted. The reaction was allowed to proceed for 30 min. at 25° C., prior to evaporation. Purification of the residue obtained by PTLC using ethylacetate:hexanes (3:7, v/v) as development solvent afforded diastereomer (6S)-5,5-dichloro-O6-5′-cyclo-5,6-dihydro-3′-fluoro-2′,3′-dideoxyuridine (R-31) and one, diastereomer of 5,5-dichloro-6-acetoxy-5,6-dihydro-3′-fluoro-2′,3′-dideoxyuridine.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][N:34]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:27])[CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[C:4]([O:28][CH3:29])[CH:3]=2)[CH2:33]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 295 mg, 0.75 mmol), ((3S)—N,N-dimethylpyrrolidin-3-amine (103 mg, 0.90 mmol) and DIPEA (0.196 mL, 1.13 mmol) were dissolved in DMA (3 mL) and sealed into a microwave tube. The mixture was heated to 100° C. for 45 minutes in a microwave reactor, then cooled to r.t., diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and then eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 2-7% methanolic ammonia in CH2Cl2 gave the title compound (235 mg, 64%) as a red solid; 1H NMR: 1.83 (1H, m), 2.17 (1H, m), 2.22 (6H, s), 2.72-2.86 (1H, m), 3.17 (2H, m), 3.26 (1H, m), 3.47 (1H, m), 3.88 (3H, s), 3.97 (3H, s), 6.58 (1H, s), 7.12 (1H, t), 7.19 (1H, d), 7.21-7.31 (1H, m), 7.52 (1H, d), 8.01 (1H, s), 8.23-8.33 (2H, m), 8.36 (1H, d), 8.58 (1H, s); m/z: ES− MH+ 488.35.
Reaction SMILES: ClC([CH:4]=[CH:5][SiH3:6])Cl.[CH3:7][S:8][CH3:9].[Cl:10][BH:11][Cl:12].[Cl:13][CH2:14][Cl:15]>>[Cl:13][CH:14]([SiH2:6][CH2:5][CH2:4][B:11]([Cl:12])[Cl:10])[Cl:15].[CH3:7][S:8][CH3:9]
Reactant: [SiH3]C=CC(Cl)Cl
Reactant: ClBCl
Reactant: ClCCl
Solvent: CSC
Product: ClB(Cl)CC[SiH2]C(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
20 ml (24.44 g; 0.173 mol) of dichloromethylvinylsilane were dissolved in 10 ml of dichloromethane and 20 ml (25.1 g; 0.173 mol) of dimethyl sulphide-dichloroborane were added dropwise at 0° C. with constant stirring. After 5 h at 0° C., the reaction mixture was heated to room temperature and, after a further 24 h, the solvent was removed under reduced pressure. The yield of [(dichloromethylsilyl)]ethyldi-chloroborane-dimethyl sulphide was quantitative.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A suspension of N-(2-methyl-4-nitrophenyl)benzamide (0.256 g, 1.0 mmol) and tin(II) chloride dihydrate (0.89 g, 3.96 mmol) in ethyl acetate (6 mL) was heated at 70° C. for 19 hr. The reaction mixture was then chilled, poured onto 50 mL ice, basified with 5% NaHCO3 (20 mL), extracted into EtOAc, washed with brine, dried and concentrated in vacuo to give N-(4-amino-2-methylphenyl)-benzamide (0.22 g, 97%). ES-MS (M+H)+=227, (M+Na)+=249.