Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:34]([C:94]([O:96][CH2:97][CH:98]1[C:110]2[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=2)[C:104]2[C:99]1=[CH:100][CH:101]=[CH:102][CH:103]=2)=[O:95])[C@H:35]([C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:91](O)=[O:92])[CH2:68][C:69](=[O:90])[NH:70][C:71]([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)=[O:65])[CH3:63])=[O:60])[C@@H:52]([CH3:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>[NH:34]([C:94]([O:96][CH2:97][CH:98]1[C:110]2[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=2)[C:104]2[C:99]1=[CH:100][CH:101]=[CH:102][CH:103]=2)=[O:95])[C@H:35]([C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:91]([NH:1][C@H:2]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:92])[CH2:68][C:69](=[O:90])[NH:70][C:71]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)[C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)=[O:65])[CH3:63])=[O:60])[C@@H:52]([CH3:58])[O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42]
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(C)(C)C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(C)(C)C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
0.4 g of H-Cys(Trt)-Pro-Wang resin are condensed in a peptide synthesizer (continuous flow principle) with Fmoc-Lys(Boc)-Thr(But)-Ala-Asn(Trt)-OH (SEQ ID NO:87), using a three-fold excess of the Fmoc peptide. The coupling is carried out at room temperature in DCCI/HOBt, to give Fmoc-Lys(Boc)-Thr(But)-Ala-Asn(Trt)-Cys(Trt)-Pro-Wang (SEQ ID NO:223) resin. Subsequent treatment with TFA/CH2Cl2 followed by removal of the Fmoc group with piperidine/DMF (20%) gives H-Lys-Thr-Ala-Asn-Cys(Trt)-Pro-OH (SEQ ID NO:92).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:28])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33]>CCOC(C)=O>[Cl:37][C:36]([Cl:39])([Cl:38])[CH2:35][O:34][C:32](=[O:33])[NH:28][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of Intermediate 75a (739 mg, 1.811 mmol) in EtOAc (9 mL) and 1N sodium hydroxide solution (4.5 mL, 4.53 mmol) was added 2,2,2-trichloroethyl chloroformate (341 μL, 2.54 mmol), and the mixture stirred vigorously at RT for 1 h. The aqueous layer was extracted with EtOAc (2×20 mL), and then the combined organics dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (743 mg, 70%). LCMS (Method 4): Rt 4.69 min, m/z 582, 584, 586 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:14][CH3:13])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CN
Product: CNCc1ccc(S(C)(=O)=O)cc1

Procedure:
(4-Methanesulfonyl-benzyl)-methyl-amine was synthesized starting from 1-bromomethyl-4-methanesulfonylbenzene and methylamine in a manner known to the skilled worker.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl.O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anisole (70.0 g) and succinic anhydride (65.0 g) were dissolved in 1,2-dichloroethane (1 liter) and the mixture was cooled to 0° C. To the resulting suspension there was added, in portions, AlCl3 (172 g) and the resulting mixture was stirred with a mechanical stirrer for 1 hour. The mixture was then poured into a mixture of ice and water (about 1 liter) containing 50 ml of concentrated HCl. The resulting white solid was collected by filtration, washed with water and air dried to yield the title compound, mp 145°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1OB(O)O.C1(C)C=CC=CC=1>C(O)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>[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[F:8]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCC[C@H]1CC[C@H](c2ccc(OB(O)O)c(F)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ccc(-c3c(F)cccc3F)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3,5-Difluorobromobenzene (30 g), tetrakis(triphenylphosphine)palladium (0) (1.8 g), ethanol (150 mL), and a 2 mol/L aqueous potassium carbonate solution (155 mL) were mixed with each other and heated to 50° C. A solution prepared by dissolving 2-fluoro-4-(trans-4-propylcyclohexyl)phenylboric acid (49.3 g) in ethanol (300 mL) was added thereto, and stirring was performed at 50° C. for five hours. After the temperature was decreased to room temperature by natural cooling, toluene (300 mL) was added thereto and the mixture was separated. The resulting organic layer was washed with a saturated saline solution (200 mL) twice. Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized using ethanol to obtain 4-[2-fluoro-4-(trans-4-propylcyclohexyl)phenyl]-3,5-difluorobenzene (39.1 g). (2-2) The subsequent processes were performed by the same method as in Example 1 to obtain [3,5-difluoro-4-(2-fluoro-4-(trans-4-propylcyclohexyl)phenyl)phenyl]-(5,6,7-trifluoro-2-naphthyloxy)difluoromethane (20.5 g).
Reaction SMILES: C(OP([CH2:9][C:10]([CH3:17])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH2:33][CH3:34])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:35](/[CH2:40][CH3:41])=[C:36](/[F:39])\[CH:37]=O)[C:20]=1[O:42][CH2:43][CH3:44]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH2:33][CH3:34])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:35](/[CH2:40][CH3:41])=[C:36](/[F:39])\[CH:37]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:42][CH2:43][CH3:44]
Reactant: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)CC
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)CC

Procedure:
Following General Procedure I-1, ethyl 4(diethoxyphosphoryl)-3-methyl-but-2-enoate (645 mg, 2.44 mmol) and (2E)-3-(4-Bromo-8-sec-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-enal (Compound A-154, 333 mg, 0.81 mmol) were reacted to give the title compound as a light yellow syrup after purification by column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[CH2:25]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:33]([N:32]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)N(Cc4ccccc4)Cc4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 74 %

Procedure:
The title compound was prepared in a yield of 74% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and N,N-dibenzylamine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24]C)[C:14]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([O:31]C)[CH:8]=[CH:7][C:6]1=2.B(Br)(Br)Br>>[OH:31][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[OH:24])[C:14]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4OC)cc1n2CCCO)C(=O)NC3=O
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2c1c(-c1ccccc1O)cc1c2c2cc(O)ccc2n1CCCO
Yield: 82 %

Procedure:
The reaction of 6-(3-Hydroxypropyl)-9-methoxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-methoxyphenyl, R10═CH2CH2CH2OH) (100) prepared as described in example 53 with BBr3 using the procedure described in example 80 gave 9-Hydroxy-4-(2-hydroxyphenyl)-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-hydroxyphenyl, R10═CH2CH2CH2OH) (101) in an 82% yield as an orange powder, mp 306–309° C. 1H NMR δ [(CD3)2SO] 10.90 (br, 1H), 9.40 (br, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.30–7.23 (m, 2H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 6.94–6.88 (m, 2H), 4.78 (br, 2H), 4.47 (t, J=6.8 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 1.91 (m, 2H). Found: C, 66.85; H, 4.61; N, 6.63. C23H18N2O5.1/2H2O requires C, 67.14; H, 4.65; N, 6.80.
Reaction SMILES: [NH2:1][C:2]([CH3:43])([CH3:42])[C:3]([NH:5][CH:6]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](F)=[CH:36][C:35]=1F)[C:7](=[O:30])[N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15](CC(F)(F)F)[C:16](=[O:17])[C:10]2([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26]N=2)[CH2:9]1)=[O:4].[C:44](O)(=O)[C@@H]([C@H](C(O)=O)O)O>>[NH2:1][C:2]([CH3:42])([CH3:43])[C:3]([NH:5][C@H:6]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:7]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][NH:15][C:16](=[O:17])[C@:10]2([CH2:23][C:24]2[CH:44]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:9]1)=[O:30])=[O:4]
Reactant: CC(C)(N)C(=O)NC(COCc1ccc(F)cc1F)C(=O)N1CCC2=NN(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: CC(C)(N)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2=NNC(=O)[C@]2(Cc2ccccc2)C1

Procedure:
2-amino-N-(1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide (U.S. Pat. No. 6,110,932) or its L-tartaric acid salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2.I[CH3:13]>>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2
Reactant: CI
Reactant: Oc1cccc2cncnc12
Product: COc1cccc2cncnc12

Procedure:
According to the procedure previously described in Example 6, 8-hydroxy-quinazoline (A1) (20 mmol) and iodomethane gave 8-methoxy-quinazoline (111). 8-Methoxy-quinazoline (111) (10 mmol) was then treated with m-chloroperbenzoic acid which gave the N-oxide 112. Subsequent treatment of the N-oxide 112 with Ac2O and phosphorus oxychloride according to Example 14 afforded 2-chloro-8-methoxy-quinazoline (113).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=1[OH:25].C(N(CC)C(C)C)(C)C>O.O1CCCC1>[Cl:1][C:2]1[C:3]([C:4]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[OH:25])=[O:6])=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])cnc2Cl)c(O)c1
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-5-nitronicotinic acid (6.1 g, 0.03 mol) and thionyl chloride (15 ml) was refluxed for 3 hours. The solvent was removed in vacuo and the acid chloride was dissolved in tetrahydrofuran (150 ml). The resulting solution was slowly added to a solution of 6-amino-m-cresol (4 g, 0.03 mol), N,N-diisopropylethylamine (7 ml, 0.04 mol), and tetrahydrofuran (150 ml) at 0° C. under argon, and the resulting solution stirred for 2 hours. The mixture was then diluted with water and the product was extracted with ether, washed with a saturated sodium chloride solution, dried (anhydrous magnesium sulfate), and concentrated to half volume. The gummy orange crude product was collected and stirred with methylene chloride (50 ml) for 30 min. The precipitate was washed with methylene chloride and air dried to give 6.3 g (68% of theory) of pure product as a bright orange powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O1CCOCC1.CCN(C(C)C)C(C)C>CO.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1COCCO1
Product: O=c1sc2cc(Br)ccc2n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a round bottom flask was added 6-bromo-1,3-benzothiazol-2(3H)-one (0.050 g, 0.217 mmol), copper(2+) diacetate (0.079 g, 0.435 mmol), [3-(trifluoromethyl)phenyl]boronic acid (0.124 g, 0.652 mmol), Dioxane (1 mL), and DIPEA (0.114 mL, 0.652 mmol). The reaction mixture was then permitted to stir open to the atmosphere for ˜17 hours (overnight). The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 30% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 6-bromo-3-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2(3H)-one (15-1) as a white solid. HRMS (M+H)+: observed=373.9455, calculated=373.9457.
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@H:11]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:39][NH2:40]>CO>[C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13]3[CH2:12][C@H:11]2[CH2:26][N:40]3[CH3:39])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C)cc1
Temperature: 90 °C
Yield: 90 %

Procedure:
A Parr bottle was charged with 115 g (198.4 mmol) of (2S, 4R)-1-(4-toluenesulfonyl)-2-(p-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 690 ml of methanol and the bottle was then tared. Methylamine gas was bubbled through the methanol solution until 62 g (2 mol) of the gas has dissolved. The bottle was then sealed and heated to 90° C. After heating for 16 hours the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were then partitioned between 500 ml of methylene chloride and 400 ml of 10% aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with 400 additional ml of 10% aqueous sodium hydroxide solution, and then dried over sodium sulfate. Evaporation of the solvent under reduced pressure provided 47.5 g of the desired product which represents a 90% yield. M.P.=87°-88° C.
Reaction SMILES: C1C2(N(C3C=CC=CC=3)CNC2=[O:8])CCN(CCCC(C2C=CC(F)=CC=2)=O)C1.CC([C@@]1(O)C[C@@H]2N(C[C@@H]3C4C2=CC=CC=4CCC2C=CC=CC3=2)CC1)(C)C.C[N:58]1[CH2:68][CH:67](C2C=CC=CC=2)[C:66]2[C:61](=[CH:62][C:63](Cl)=[C:64]([OH:75])[CH:65]=2)CC1.CN1C[C@H](C2C=CC=CC=2)C2C=C(O)C(Cl)=CC=2CC1>>[NH2:58][CH2:68][CH2:67][C:66]1[CH:61]=[CH:62][C:63]([OH:8])=[C:64]([OH:75])[CH:65]=1
Reactant: O=C(CCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2ccccc2)C1
Agent: CC(C)(C)[C@]1(O)CCN2C[C@H]3c4ccccc4CCc4cccc(c43)[C@@H]2C1
Agent: CN1CCc2cc(Cl)c(O)cc2[C@@H](c2ccccc2)C1
Product: NCCc1ccc(O)c(O)c1

Procedure:
The following tritiated drugs were used as radioligands for each of the receptors tested: [3H]-Spiperone 21-24 Ci/mmol for D2 receptors and [3H]-SCH23390 75-85 Ci/mmol for D1 receptors. The radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of time as follows: 75 minutes at room temperature for D2 receptors or 15 minutes at 37° C. for D1 receptors. Specific binding was defined using 1 μM butaclamol (D2) or 1 μM SCH23390 (D1). In addition, the D2 assays contained 30 nM ketaserin in order to block the binding of 3H-spiperone to 5HT2 receptors.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](Br)=[CH:18]4)=[CH:13][C:12]=3[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[BH:30]([OH:32])[OH:31]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([B:30]([OH:32])[OH:31])=[CH:18]4)=[CH:13][C:12]=3[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: OBO
Product: CC(C)(C)[Si](C)(C)Oc1cc2ccc(B(O)O)cc2cc1C12CC3CC(CC(C3)C1)C2

Procedure:
Following the basic procedure of Example 7(e), beginning with 11.9 g (25.4 mmol) of 7-(1-adamantyl)-6-tert-butyldimethylsilyloxy-2-bromonaphthalene, 8.37 g (75%) of the expected boronic acid of melting point 221°-222° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O.P(Cl)(Cl)(Cl)=O>>[N:19]1[CH2:23][CH2:22][CH2:21][C:20]=1[N:6]1[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Reactant: O=C1CCCN1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2c(c1)N(C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE as a distillable oil, b.p. 140°-146° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 219.5°-222.5° C. (dec.)(corr.), in a 62% overall yield by triturating with warm benzene.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O>Cl.C(OCC)(=O)C.[OH-].[Na+]>[NH2:1][C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[CH:6][CH:5]=1
Reactant: C=CCOC(=O)c1ccc([N+](=O)[O-])s1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1ccc(N)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
To a solution of allyl 5-nitro-2-thiophenecarboxylate (3.2 g, 15 mmol) in concentrated hydrogen chloride (35 ml) was added, under cooling, SnCl2.H2O (10.1 g, 45 mmol). The mixture was stirred for 3.5 hours at ambient temperature, diluted with ethyl acetate and basified to pH 10 with 5N NaOH. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (3:7) to give the title compound as a yellow oil (1.94 g, 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
Piperidin-2-yl-methanol (60.77 mmol, 1 eq) was dissolved in methylene chloride (150 ml) and triethylamine (151.92 mmol, 2.5 eq) at 0° C. and a solution of 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (60.77 mmol, 1 eq) in methylene chloride (50 ml) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 14 h. The reaction solution was then diluted with methylene chloride (200 ml) and the organic phase was washed with saturated sodium chloride solution (2×50 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (5-20% ethyl acetate in hexane). Yield: 63%
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[C:21]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([C:28]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCNc2ccccc2-4)cc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCc2cnc3[nH]ncc3c2-c2ccccc21
Yield: 19 %

Procedure:
The compound, 8-(phenylcarbonyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine was prepared using 3-(4-methoxybenzyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine and bezoyl chloride using the 2 step conditions described in general procedure R to give the desired product as a white solid (0.028 g, 19%). M.p.>150° C.; 1H NMR (CDCl3, 400 MHz) δ: 11.25 (brs, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.84 (dd, J1=1.2 Hz, J2=8.0 Hz, 1H), 7.41 (m, 1H), 7.21-7.07 (m, 6H), 6.82 (d, J=7.2 Hz, 1H), 4.74 (m, 1H), 3.92 (m, 1H), 3.00 (m, 2H); LCMS [M+H]: 341.