Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([F:21])=[C:6]([F:20])[C:7]([N:12]2[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]2)=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CC(O)C>[C:1]([C:4]1[CH:11]=[C:8]2[C:7](=[C:6]([F:20])[C:5]=1[F:21])[N:12]1[CH2:17][C@@H:16]([CH3:18])[O:15][C@@H:14]([CH3:19])[C@@H:13]1[C:28]1([C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]1=[O:30])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C=O)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: CC(=O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Temperature: 85 °C

Procedure:
To a solution of 5-acetyl-2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde (Intermediate 11, 3.0 g, 9.17 mmol) in IPA was added barbituric acid (1.4 g, 11.00 mmol), and the mixture was heated at 85° C. for 12 hours. Solvents were evaporated and the residue was purified over neutral alumina using a gradient of methanol in CH2Cl2 to give the title compound as a racemic mixture in the form of an off-white solid. Yield: 3.0 g (75%).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([C:10]([O-:12])=O)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Li+].C(C1N=C(C([Cl:24])=O)SC=1)(C)C>>[CH:1]1([C:5]2[N:6]=[C:7]([C:10]([Cl:24])=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: O=C([O-])c1nc(C2CCC2)cs1
Agent: [Li+]
Product: O=C(Cl)c1nc(C2CCC2)cs1

Procedure:
4-Cyclobutylthiazole-2-carbonyl chloride 267b was synthesized from compound 266b (5 g, 1 eq.), following the procedure as described for compound 214. MS (ESI, EI+): m/z=198 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1cccs1
Reactant: Brc1nccc(Nc2cc(C3CC3)[nH]n2)n1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1csc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 50.8 %

Procedure:
A mixture of 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (170 mg, 0.64 mmol, 1.0 equiv.), thiophen-2-ylboronic acid (107 mg, 0.83 mmol, 1.3 equiv.), Pd(PPh3)4 (148 mg, 0.128 mmol, 0.2 equiv.), Na2CO3 (238 mg, 2 mmol, 3.5 equiv.), 1,4-dioxane (5 ml) and water (1 ml) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool down to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1 as eluent) to afford title compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(thiophen-2-yl)pyrimidin-4-amine (Compound 27)(92.2 mg, 50.9%) as solid. LC-MS (m/z)=284.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.71 (m, 2H), 0.95 (m, 2H), 1.94 (m, 1H), 6.35 (s, 1H), 6.87 (s, 1H), 7.17 (m, 1H), 7.70 (m, 1H), 7.83 (d, J=2.8 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 9.91 (s, 1H), 12.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:37][C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40](Cl)[N:39]=2)=[C:29]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:37][C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40]([NH:1][C:2]3[C:21]([O:22][CH3:23])=[CH:20][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[O:13])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:39]=2)=[C:29]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])[CH:30]=1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(Cl)cc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCOCC1)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.034 g, 24%). MP: 100-115° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.21 (s, 1H), 8.45 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.93 (s, 1H), 7.87-7.85 (m, 1H), 7.53-7.47 (m, 2H), 6.65 (s, 1H), 3.88 (s, 3H), 3.75-3.62 (m, 9H), 3.30 (s, 2H), 2.90-2.85 (m, 2H), 2.77 (s, 6H), 2.75-2.63 (m, 6H). MS: 664.19 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:43])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][N+:28]([CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=4)=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([O-:17])=[O:16])=[O:4].[CH3:44][N:45]1[CH:49]=[N:48][N:47]=[C:46]1[SH:50].C(N(CC)CC)C>CN(C)C=O>[F:41][C:36]1[CH:35]=[C:34]([NH:33][C:32]([CH2:31][N+:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23]/[C:19](=[CH:18]\[C:10]4[CH2:9][S:8][C@H:7]5[N:12]([C:13](=[O:14])[C@H:6]5[NH:5][C:3](=[O:4])[CH2:2][S:50][C:46]5[N:45]([CH3:44])[CH:49]=[N:48][N:47]=5)[C:11]=4[C:15]([O-:17])=[O:16])/[C:20]3=[O:43])=[CH:30][CH:29]=2)=[O:42])[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Reactant: Cn1cnnc1S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnnc1SCC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reaction time: 12 h

Procedure:
To a solution of 230.0 mg (0.34 mmol) (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate in 5 ml N,N-dimethylformamide was added 40.0 mg (0.37 mmol) 4-methyl-4H-[1,2,4]triazole-3-thiol. After 1 h 47.0 μl (0.34 mmol) triethyl amine was added and stirring was continued for 12 h. The solution was poured on diethyl ether and the resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:22][CH3:23])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 78.13 mmol) in DMF (200 mL) was added potassium carbonate (23.7 g, 171.74 mmol), followed by dropwise addition of iodoethane (3.6 mL, 44.54 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (6:1 to 3:1) to give 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 40.7% yield) as yellow solid. LCMS retention time 0.402 min; LCMS MH+ 221.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([NH:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(N)CC2)nc1N
Reactant: CS(=O)(=O)Cl
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(NS(C)(=O)=O)CC2)nc1N

Procedure:
The similar procedure as described in Example 60 was used, starting from [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 345) and methanesulfonyl chloride (Aldrich) to give N-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-methanesulfonamide. MS (M+H)+, 452.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:32](=[O:33])[CH2:31][O:30][C:29]5[CH:35]=[CH:36][C:26]([Cl:25])=[CH:27][CH:28]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Fc1ccc(CCc2nc3c(N4CCNCC4)ncnc3s2)cc1
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(CCc4ccc(F)cc4)nc23)CC1
Yield: 48 %

Procedure:
This compound was prepared from 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.
Reaction SMILES: CN(C)C(N1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([NH2:26])[C:20]=4[CH3:27])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.ClC1C2C=C(C3CC[C:43]4([O:47][CH2:46][CH2:45][O:44]4)CC=3)NC=2N=CN=1>>[O:44]1[C:43]2([CH2:6][CH2:7][C:8]([C:11]3[NH:28][C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=5)[C:13]=4[CH:12]=3)=[CH:9][CH2:10]2)[O:47][CH2:46][CH2:45]1
Reactant: Clc1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Product: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12

Procedure:
Intermediate 18 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 17.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:14]([CH2:12][CH3:13])[CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:18])([F:20])[F:19])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1Cl

Procedure:
Prepared similarly to Example 48 from 2-chloro-6-fluorobenzoylchloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])CC2C=CC=CC=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[O:33][C:32]([F:43])([F:42])[F:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: FC(F)(F)Oc1ccccc1CBr
Product: OC(Cc1ccccc1OC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-(trifluoromethoxy)benzyl bromide (available from Fluorochem) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=458.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])([CH3:23])C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1([CH3:23])[CH2:28][O:27][C:25](=[O:26])[NH:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCc1ccccc1OCc1ccccc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CCc2ccccc2OCc2ccccc2)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a solution of ethyl 4-(2-benzyloxyphenyl)-2-methoxycarbonylamino-2-methylbutanoate (5.2 g) in tetrahydrofuran (135 ml), under a nitrogen atmosphere, lithium borohydride (0.59 g) was added and the mixture was refluxed under heating for an hour. Then, a 2N hydrochloric acid (6.6 ml) was added thereto and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (4.6 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)([N:10]1[CH:14]=[CH:13]N=[CH:11]1)=[O:9].Cl.N1CC[CH:24]([O:27][C:28]2[N:33]=[CH:32][N:31]=[C:30]([N:34]3[C:42]4[C:37](=[CH:38][C:39]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:41]=4)[CH2:36][CH2:35]3)[CH:29]=2)[CH2:23]C1>C1COCC1>[N:15]1([C:8]([N:10]2[CH2:11][CH2:23][CH:24]([O:27][C:28]3[N:33]=[CH:32][N:31]=[C:30]([N:34]4[C:42]5[C:37](=[CH:38][C:39]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:41]=5)[CH2:36][CH2:35]4)[CH:29]=3)[CH2:13][CH2:14]2)=[O:9])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
Triethylamine (286 μL, 2.05 mmol) and 1,1′-carbonyldiimidazole (249 mg, 1.54 mmol) were added to a THF (9.00 mL) solution of the 1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]-5-(propylsulfonyl)indoline hydrochloride (450 mg, 1.03 mmol) produced in Reference Example 32, and the mixture was stirred at room temperature for 3 hours. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, water was added, and the mixture was stirred. The deposit was collected by filtration and washed with water to obtain the title compound as white powder (291 mg, yield: 57%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc([N+](=O)[O-])ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-nitro-biphenyl-3-yl)-acetic acid ethyl ester and benzyl chloroformate.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:20][C:21]#[N:22])[CH:12]=[CH:11]1>O1CCCC1.Cl.O>[CH:2]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:20][C:21]#[N:22])[CH:12]=[CH:11]1)=[O:1]
Reactant: N#CCOc1cccc2ccn(Cc3cccc(C4OCCO4)c3)c12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#CCOc1cccc2ccn(Cc3cccc(C=O)c3)c12

Procedure:
A solution of 1-[3-(1,3-dioxolan-2-yl)benzyl]-7-cyanomethoxyindole (50 mg., 0.15 mmol) in tetrahydrofuran (1 ml) and 2M hydrochloric acid (0.5 ml) was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The extract was dried and evaporated to a dark oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][C:9]1[NH:23][CH2:22][CH2:21][C:11]2=[C:12]3[C:17](=[N:18][C:10]=12)[CH:16]=[CH:15][C:14]([O:19][CH3:20])=[CH:13]3>C(O)=O>[CH2:8]=[C:9]1[C:10]2[NH:18][C:17]3[C:12](=[CH:13][C:14]([O:19][CH3:20])=[CH:15][CH:16]=3)[C:11]=2[CH2:21][CH2:22][N:23]1[CH:1]=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Solvent: O=CO
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (1 ml) cooled to 0° C. is added dropwise formic acid (0.5 ml). The mixture is heated for 15 min. at 50° C. After cooling rapidly to 0° C., 10-methoxyharmalan (200 mg) is added slowly and portionwise and the medium is left stirring for 2 h. The crude product is then taken to dryness and, after separation by chromatography (eluent: EtOAc/pet. ether; 50/50), 1-methylene-2-formyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].Br[CH2:13][CH:14]1[CH2:16][O:15]1>CN(C=O)C>[O:15]1[CH2:16][CH:14]1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: BrCC1CO1
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (2.0 g, 16.38 mmol) in DMF (30 mL) at 0° C. was added NaH (983 mg, 24.57 mmol) in portions. After 0.5 h, a solution of 2-(bromomethyl)oxirane (2.69 mg, 19.65 mmol) in DMF (5 mL) was added and the reaction mixture was warmed to room temperature for 5 h. The mixture was concentrated, dissolved in ethyl acetate and washed with water. The organic portion was dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification. (2.1 g, yield 72%) MS (ESI+) e/z: 179.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:12]2[N:13]=[CH:14][N:15]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:16]=2)=[CH:9]/[O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].Cl>ClCCl>[CH2:29]([S:31]([NH:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:12]2[N:13]=[CH:14][N:15]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])[CH:16]=2)=[CH:9]/[O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CCS(=O)(=O)Cl
Reactant: CO/C=C(/c1cccc(N)c1)c1cn(S(=O)(=O)N(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(/C(=C/OC)c2cn(S(=O)(=O)N(C)C)cn2)c1
Reaction time: 5 h

Procedure:
A solution of Example 46B (0.32 g, 0.99 mmol) in dichloromethane (5 mL) was treated with pyridine (0.24 mL, 3.0 mmol), treated with ethanesulfonyl chloride (0.10 mL, 1.1 mmol), stirred for 5 hours, treated with 1M HCl and extracted with dichloromethane (3×). The combined dichloromethane extractions were dried (Na2SO4) and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:25])([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:25]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 358.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:19][N:20]=2)[N:17]=1>CN(C=O)C>[CH3:3][N:4]1[C:8]([CH2:9][O:10][C:12]2[C:13]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[N:19][N:20]=3)[N:17]=2)=[N:7][CH:6]=[N:5]1
Reactant: Clc1nn2c(-c3cccnc3)nnc2cc1N1CCCC1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3cccnc3)nnc2cc1N1CCCC1
Reaction time: 18 h
Yield: 60.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 16 mg, 0.41 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (EP-A-421210; 40 mg, 0.35 mmol) in dry DMF (2 ml) at room temperature. After 1 h at room temperature a solution of 6-chloro-3-(pyridin-3-yl)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.33 mmol) was added and the reaction stirred for 18 h. The residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (2×100 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0-10% ethyl acetate-methanol to afford the title pyridazine (75 mg, 60%). 1H NMR (250 MHz, CDCl3) 1.99-2.04 (4H, m), 3.52-3.57 (4H, m), 4.01 (3H, s), 5.65 (2H, s), 6.69 (1H, s), 7.57 (1H, q, J=7.7, 4.8 Hz), 7.97 (1H, s), 8.60-8.68 (2H, m), 9.51 (1H, d, J=1.6 Hz); MS (ES+) 378 [MH]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][O:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1.[I:15]I>N1C=CC=CC=1.CCOCC>[I:15][C:10]1[C:11](=[O:14])[O:12][CH2:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(C2=CC(=O)OC2)cc1
Reactant: II
Solvent: CCOCC
Solvent: c1ccncc1
Product: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reaction time: 24 h

Procedure:
To a solution of 3 g of the product of Step 2 in 30 ml of pyridine is added 8.7 g of I2. The mixture is stirred for 24 h and then diluted with 200 ml of ether, washed with 100 ml of 5N HCl and 50 ml of 5N Na2S2O3. The ether layer is dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [O-]S([O-])(=O)=O.[Zn+2:6].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([OH:15])=[O:14].[Zn]>O>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([O-:15])=[O:14].[Zn+2:6].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([O-:15])=[O:14]
Reactant: O=C(O)c1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: O=C([O-])c1ccccn1
Reaction time: 0.07 h

Procedure:
Thirty grams of ZnSO4 ·7H2O was dissolved in 200 ml. deionized water at room temperature. Thereafter, 20 g. picolinic acid (Sigma Chemical, St. Louis, MO) was added to the solution and the solution was stirred continuously. Within 3-5 minutes a precipitate began to form. After 30 minutes the stirring was discontinued and the mixture was left standing at room temperature until the precipitate had settled to the bottom. The supernatant was removed by aspiration and the precipitate was suspended in enough deionized water to yield 200 ml. This suspension was then heated in a beaker with continuous stirring until the precipitate had completely dissolved after which the beaker was placed in an ice bath and stored overnight in a cold room (4°). The following morning the supernatant was aspirated from the crystals and the crystals were freeze dried. Assay of the crystals proved that the complex contained 2 moles of picolinic acid and 1 mole of zinc [zinc dipicolinate, Zn(PA)2 ].