Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][Cl:28])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: O=C(Cl)CCCCl
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A solution of 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.2 g, 4.3 mmol, 1 equiv) in CH2Cl2 (10 ml) was treated with NEt3 (525 mg, 5.2 mmol, 1.2 equiv). The solution was cooled to 0° C. and 4-chlorobutyryl chloride (733 mg, 5.0 mmol, 1.2 equiv) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The solution was washed with 2N aqueous HCl solution (20 ml), dried over MgSO4 and concentrated in vacuo to give 5-(4-chloro-butanoylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D89) (1.7 g, 104%) as a colourless oil.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[NH:18][C:17]3=[O:25])=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.I[CH2:27][CH3:28]>O>[CH2:27]([N:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:13]2[CH:14]=[CH:15][C:10]([N:1]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[CH:3]=[N:2]3)=[CH:11][CH:12]=2)[C:17]1=[O:25])[CH3:28]
Reactant: CCI
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(-n2ncc3cccnc32)cc1
Solvent: O
Product: CCn1c(=O)n(-c2ccc(-n3ncc4cccnc43)cc2)c2ncccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg) and iodoethane (10.5 μl) was stirred at 50° C. for 30 min, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with Hexane/AcOEt=2/1-1/2. The product was crystallized from AcOEt/hexane to give 1-ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (13 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:41]=1)[C:36]([OH:38])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:57][N:58]1[CH:62]=[CH:61][C:60]([NH2:63])=[N:59]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:47]([CH3:49])[CH3:48])[CH:50]([CH3:52])[CH3:51])[CH:41]=1)[C:36]([NH:63][C:60]1[CH:61]=[CH:62][N:58]([CH3:57])[N:59]=1)=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
HATU (23.5 g, 61.8 mmol) was added to 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoic acid (23.6 g, 51.5 mmol), followed by addition of DMF (140 mL), and cooled to 0° C. 1-Methyl-1H-pyrazole-3-amine (6.00 g. 61.8 mmol) was added followed by DIPEA (21.3 mL) and the reaction was stirred under argon at 0° C. for 3 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (500 mL) and washed with citric acid solution (200 mL), sodium hydrogen carbonate solution (150 mL), and saturated brine solution (2×150 mL). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (21.7 g). 1H NMR δ (CDCl3): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.3 (d, 3H), 3.7 (m, 1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.5 (m, 1H), 5.1 (s, 2H), 6.7 (s, 1H), 6.8 (s, 1H), 7.0 (m, 2H), 7.1 (s, 1H), 7.3 (s, 1H), 7.35-7.5 (m, 5H), 8.5 (s, 1H). m/z 538 (M+H)+
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH:28]4[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:30][CH:22]3[CH2:23]5)[CH2:27]4)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[CH:22]12[CH2:30][CH:26]3[CH2:25][CH:24]([CH2:29][CH:28]([CH2:27]3)[CH:21]1[NH:20][C:19](=[O:31])[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:9]3[CH2:8][CH2:7][CH:6]([CH2:4][OH:3])[CH2:11][CH2:10]3)=[CH:14][CH:15]=1)[CH2:23]2
Reactant: CCOC(=O)C1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(OC2CCC(CO)CC2)cc1
Temperature: -35 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
In a flame dried flask was 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester (2 g, 4.7 mmol) dissolved in dry THF (300 mL) and cooled to −35° C. To this solution was added 1M DIBAL in toluene (14 mL, 14.1 mmol) and the mixture was stirred at −35° C. for 3 hrs. and left in a freezer at −18° C. for 16 hrs. Due to incomplete reaction an additional portion of 1M DIBAL (5 mL) was added and the mixture was stirred at −18° C. for 1 hr. The reaction was quinched by slowly addition of sat. aq. NH4Cl followed by evaporation to ¼ of the volume and extracted with DCM (3×50 mL). The combined organic phases were evaporated in vacuo and the residue purified using column chromatography (Isco, 120 gram column) and a solvent gradient of heptane/AcOEt from 0 to 100%. Desired fractions were collected and the solvent evaporated in vacuo affording 1 g (60%) of N-adamantan-2-yl-4-(4-hydroxymethyl-cyclohexyloxy)-benzamide as an oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>C(O)(=O)C>[O:14]=[C:10]1[CH:11]([CH3:12])[C:4]2[C:3](=[CH:2][C:1]([NH:8][C:12](=[O:13])[CH2:11][C:10]([CH3:9])=[O:14])=[CH:6][CH:5]=2)[NH:7][CH2:9]1
Reactant: Nc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)Nc1ccc2c(c1)NCC(=O)C2C
Temperature: 15 °C
Yield: 83 %

Procedure:
129.6 gm of at least 98 percent pure 1,3-phenylene diamine (melting point: 60° to 62° C) and 750 ml of 10 percent acetic acid were placed in a sulfurizing flask, equipped with an anchor bolt, reflux cooler, drip funnel, thermometer and water bath. 211.2 gm of diketene were allowed to drip into the reaction mixture over the course of 1.5 hours at room temperature. The reaction was stirred during the addition. The temperature, with the aid of the reaction heat, was allowed to rise to 60° to 65° C. After completion of the addition of diketene, the mixture was allowed to continue for another hour at 60° to 65° C. and was then cooled to about 15° C. The precipitated product was then separated out and dried under vacuum at 60° to 70° C. until the precipate reached a constant weight. 257 gm. of raw, almost colorless, 1,2-dihydro-3oxo-4-methyl-7-acetoacetamido-quinoline was obtained having a melting point of about 238° C. This corresponded to a yield of about 83 percent, based on the m-phenylene diamine. After a single recrystallization from 67 percent acetic acid, the product had a melting point of 246.0° to 247.0° C. After one more recrystallization from the diluted acetic acid, the melting point was found not to have changed.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:5]=1
Reactant: Cc1cc(O)nc(/C=C/c2cccs2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2cccs2)n1
Yield: 57.3 %

Procedure:
In analogy to example 12c), by heating (E)-6-methyl-2-(2-thiophen-2-yl-vinyl)-pyrimidin-4-ol (0.38 g, 1.74 mmol) in POCl3 (3.19 ml, 34.8 mmol) at 130° C. for 4.5 h was obtained (E)-4-chloro-6-methyl-2-(2-thiophen-2-yl-vinyl)-pyrimidine (0.236 g, 57%) as a light yellow solid. EI mass spectrum, m/e: 236 (M calculated for C11H9ClN2S: 236).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[B:10](OC)([O:13]C)[O:11]C.Cl>C1COCC1.[Cl-].[Na+].O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([B:10]([OH:13])[OH:11])[CH:9]=[CH:8][CH:7]=1
Reactant: COB(OC)OC
Reactant: OCc1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Bromobenzyl alcohol (2.0 g, 10.7 mmol) was dissolved in dry THF (50 ml) in a dry 100 ml flask flushed with nitrogen. The mixture was chilled in a dry ice/acetone bath. n-Butyl lithium (11 ml of a 2.13M solution in hexane, 23.5 mmol) was added. The reaction was warmed to room temperature for 1 hour, then cooled in an ice water bath. Trimethyl borate (1.3 ml, 11.2 mmol) was added and the mixture was stirred at room temperature overnight, then treated with 2N aqueous HCl to pH 2, and stirred for 3 hours. Brine (15 ml) was added, and the mixture was extracted with ethyl acetate (3×15 ml). The organic materials were combined, dried (MgSO4) then concentrated under reduced pressure which gave of 3-hydroxymethylbenzeneboronic acid (98%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N+:6]([O-])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[NH2:1][C:2]1[C:7]([Cl:13])=[N:6][CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1c[n+]([O-])cc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnc(Cl)c(N)n1

Procedure:
A suspension of 2-amino-6-methoxypyrazine 4-oxide in freshly distilled phosphorus oxychloride is refluxed for one hour. Thin layer chromatography indicates that the starting material is no longer present. The excess of phosphorus oxychloride is removed in vacuo and the residue is treated with crushed ice. If decomposition is complete the solution is made alkaline with 10% sodium hydroxide and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and evaporated to give the product which may be recrystallized from a suitable solvent such as ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13]C1C=CC2CCN(C3CCC3)CCC=2C=1)[C:6]([NH:8][CH3:9])=[O:7])#[N:2].B(Br)(Br)Br.O.Cl>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([NH:8][CH3:9])=[O:7])#[N:2]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(C#N)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(O)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
3-Cyano-N-methyl-4-(methyloxy)benzamide (E279, Step 2) (346 mg, 1.82 mmol), was dissolved in dry dichloromethane (10 ml), cooled to 0° C. and treated with boron tribromide (1 M solution in dichloromethane) (9.11 ml, 9.11 mmol). The mixture was stirred for 30 minutes, allowed to warm to room temperature and stirred for 18 hours. The mixture was cooled in an ice bath, treated with water added dropwise and then allowed to warm to room temperature. The mixture was poured onto 2M hydrochloric acid (10 ml) and extracted with ethyl acetate. The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate dichloromethane (1:1) to afford the title compound (86 mg); MS (ES+) m/e 177 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:49])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH3:35])=[S:33])=[CH:27][C:26]=1[O:36][CH2:37][CH2:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8]>CCOCC.C1COCC1>[C:7]([O:11][C:12](=[O:49])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH3:35])=[S:33])=[CH:27][C:26]=1[O:36][CH2:37][CH2:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CNC(=S)Nc1ccc(S(=O)(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC)c(OCCc2cccc3ncccc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 505.8 %

Procedure:
A mixture of 2 mL THF and 0.8 mL 1M LiAlH4 solution in ether was cooled to −65° C. in a chloroform/dry ice bath. A mixture if 0.18 g (0.29 mmol) N-methoxy-N-methyl--3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-succinamic acid tert-butyl ester in 3 mL THF was added dropwise and the reaction mixture was stirred 30 min at −65° C. TLC analysis showed starting material consumed. The reaction was quenched cold with 1 mL 1M aqueous potassium sodium tartrate solution and allowed to reach room temperature. The product was partioned between 75 mL brine and 50 mL EtOAc. The product was extracted with 50 EtOAc, the combined organic extracts dried over anhydrous magnesium sulfate, filtered, concentrated and purified on silica with 1:1 EtOAc:hexanes to give 0.84 g (52%) of 3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a colorless glass. MS (APCI) m/z 573 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44]([OH:46])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][NH2:48]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44](=[O:46])[NH:48][CH3:47])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: CNC(=O)CC[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1

Procedure:
Similar to example 6a, 80.0 mg of (2R,4R,5R)-2-(2-carboxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1 carboxylic acid benzyl ester are reacted with methylamine to afford the title compound as a yellow oil. Rf=0.35 (dichlormethane-methanol 9:1); Rt=4.69.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([F:17])[CH:11]=1.N1C=CC=CC=1>ClCCl>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[C:12]([F:17])[CH:11]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
3-chloropropane-1-sulfonyl chloride (3.16 ml, 0.026M) was added to a solution of 4-bromo-2-fluoroaniline (5.00 g, 0.026M) and pyridine (2.12 ml, 0.026M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (8.3 g). 1H NMR (CDCl3): δ 2.54 (m, 2H), 2.90 (m, 2H), 3.64 (d, J=2.56 Hz, 2H), 6.91 (d, J=3.56 Hz, 1H), 7.07 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:13][CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH3:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(C)O)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)OS(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Into a THF solution (35 ml) of 1-(3-methyl-4-nitrophenyl)-ethanol (5.44 g) and triethylamine (3.95 g), a THF solution (10 ml) of methanesulfonyl chloride (3.48 g) was added dropwise at 5° C. over a period of 30 minutes. Further, the mixture was stirred at room temperature for 8 hours. After finishing the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate (100 ml). It was washed with 2N aqueous solution of hydrochloric acid and saturated aqueous solution of sodium bicarbonate and then dried with anhydrous magnesium sulfate. After distilling off the solvent, the aimed 1-(3-methyl-4-nitrophenyl)-ethyl methanesulfonate (5.80 g) was obtained.
Reaction SMILES: C(OC(N1CCC2(OCCN([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)C2)CC1)=O)(C)(C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][C:47]2([CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[O:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH2:48][C:47]2([CH2:53][CH2:52][N:51]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:50][CH2:49]2)[O:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Reactant: CC(C)(C)OC(=O)N1CCOC2(CCNCC2)C1
Product: CC(C)(C)OC(=O)N1CCOC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester using 1-oxa-4,9-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester in place of 4-ethoxy-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (110 mg, 60%).
Reaction SMILES: C(O)(=O)C.CN(C)[CH:7]=[CH:8][CH:9]=O.[CH:12]([C:15]1[C:16]([NH2:21])=[N:17][NH:18][C:19]=1[NH2:20])([CH3:14])[CH3:13]>C(O)C>[CH:12]([C:15]1[C:16]([NH2:21])=[N:17][N:18]2[CH:9]=[CH:8][CH:7]=[N:20][C:19]=12)([CH3:14])[CH3:13]
Reactant: CN(C)C=CC=O
Reactant: CC(C)c1c(N)n[nH]c1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1c(N)nn2cccnc12

Procedure:
Acetic acid (0.038 mL, 0.67 mmol) was added to a solution of 3-dimethylaminoacrylaldehyde (624 mg, 4.43 mmol) and the product from Example 112B (414 mg, 2.95 mmol) in ethanol (9 mL), and the reaction mixture was heated at 80° C. for 4 hours, then concentrated under vacuum to a dark oil. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc 50:50-0:100) to provide the title compound as a yellow solid. MS (ESI) m/z 177 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 4-(4-bromophenyl)piperidin-4-ol is placed in 20 ml of dichloromethane. 0.65 ml of triethylamine and then 0.33 ml of methanesulphonyl chloride are added. The reaction mixture is stirred at ambient temperature for 2 h. It is washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and then evaporated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a dichloromethane/methanol (99/1) solvent mixture. 1.1 g of 4-(4-bromophenyl)-1-(methanesulphonyl)piperidin-4-ol are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F-:15].[K+]>[Br-].C[N+](C)(C)C>[F:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: C[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Temperature: 165 °C

Procedure:
A mixture of 22.6 parts of 4-chloro-3-nitrobenzotrifluoride, 9.3 parts of potassium fluoride, and 1.4 parts of tetramethylammonium bromide catalyst was heated and maintained at about 165.0° C. for about 9 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was distilled under reduced pressure to yield 161 parts of 4-fluoro-3-nitrobenzotrifluoride.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:6].Cl.N[OH:23]>C(O)C>[OH:6][C:5]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[O:23][N:2]=[CH:3][CH2:4]1
Reactant: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C1(O)CC=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 3-dimethylamino-1-(2-nitro-4-trifluoromethylphenyl)-prop-2-en-1-one (41.0 g) and hydroxylamine hydrochloride (11.9 g) in dry ethanol (280 ml) was stirred at room temperature overnight. It was evaporated to dryness and the residue was dissolved in a mixture of ether (150 ml) and water (100 ml). The layers were separated and the organic layer was washed with water (100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit (bp 60°-80° C.) (20 ml) and filtered to give 5-hydroxy-5-(2-nitro-4-trifluoromethylphenyl)-isoxazoline (33.9 g) as a pale yellow solid mp 122°-123° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH3:6]>CC(O)=O>[CH2:5]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([OH:17])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=2[CH2:8]1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCC1CCc2cc(O)ccc2C1
Solvent: CC(=O)O
Product: CCC1CCc2cc(O)c([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of HNO3 (65%, 1.05 mL, 23.0 mmol) in AcOH (10 mL) at 0° C. is added 6-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (2.02 g, 11.5 mmol) in AcOH (33 mL) dropwise. It is allowed to warm to ambient temperature and stirred for 1.5 h and then at 40° C. until starting material is completely consumed. Water is added, followed by EtOAc. The organic layer is concentrated and purified by column chromatography to give the title compound as a yellow oil: 1H NMR (CDCl3) δ 0.91 (t, J=7 Hz, 3H), 1.28-1.36 (m, 3H), 1.51-1.56 (m, 1H), 1.85-1.90 (m, 1H), 2.24-2.31 (m, 1H), 2.72-2.64 (m, 3H), 6.77 (s, 1H), 7.73 (s, 1H), 10.29 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH3:26][CH:27]=[CH:28][CH2:29][NH2:30]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:29][CH2:28][CH:27]=[CH2:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 32, 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-bromo-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.